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Beni-Suef University Journal of Basic and Applied Sciences
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Synergistic strategies for cancer treatment: leveraging natural products, drug repurposing and molecular targets for integrated therapy

Beni-Suef University Journal of Basic and Applied Sciences volume 13, Article number: 96 (2024) Cite this article

Abstract

Background

Uncontrolled cell proliferation is a major cause of cancer development and progression. Inflammation along with inflammatory mediators and cells play a significant role in cancer. Cancer ranks in second in mortality rates, following cardiac diseases. Phytochemicals from medicinal plants offer a natural and effective approach for treating Inflammation and cancer.

Main body of the abstract

Animal studies provide evidence that phytochemicals present in food acts as antioxidants, anti-aging molecules, and health promoters, thereby extending lifespan. These natural compounds include quercetin, epicatechin, resveratrol, curcumin, kaempferol, vitamin C and carotenoids. However, clinical data on humans is still awaited. Conventional allopathic cancer therapies often have severe side effects. Recently, drug repurposing has emerged as an alternative strategy offering lower costs, shorter development times and the advantage of existing clinical data. The primary goal of drug repurposing is to discover new uses for approved or experimental drugs.

Short conclusion

The current review elucidates the side effects of synthetic drugs and the beneficial effects of phytochemicals and non-oncological drugs along with their mechanisms of action for treating cancer. Additionally, it highlights clinical trial data for various cancers focusing on molecular targets. By integrating natural products, drug repurposing and molecular targets, we can develop multifaceted therapies that maximize efficacy and minimize adverse effects. This integrated approach promises more personalized and effective treatments, improving patient outcomes and quality of life. Future research should identifying novel natural compounds, explore repurposing opportunities for existing drugs, and elucidate molecular targets for precise therapy. Additionally, clinical trials should be conducted to validate the efficacy and safety of these combined strategies in cancer patients.

Graphical abstract

1 Background

Cancer is one of the common diseases with the mortality rate increasing every year, accounting for 19.3 million new cancer cases worldwide. In recent years, cancer has become the second leading cause of death after cardiac failure and by the end of 2030, cancer cases are expected to double [1]. Chemotherapy, radiation and surgery are common cancer treatments, but each has significant drawbacks, such as severe side effects, damage to healthy tissues, and the risk of cancer recurrence [2]. In 1863, Rudolf Virchow identified the role of inflammation in cancer progression by observing leukocytes in cancer tissues. It is well known that inflammation is a preliminary process in wound healing [3]. In the context of cancer, inflammation induces a homeostatic response due to an increased number of macrophages and fibroblasts at the infection site. The infiltration of macrophages and fibroblasts is mediated by signaling molecules, such as cytokines and chemokines. This process occurs during infection, wounding and tumor growth. Among all cancer types, 15–20% are anticipated to be driven by inflammation, infection and autoimmunity [4]. In recent times, cancer has emerged as a significant medical concern, second only to cardiac diseases [5]. Conventional anticancer therapies often lead to significant adverse effects and offer limited extension to patients’ life span, typically only by a few years. Hence, there’s burgeoning scientific and commercial interest in exploring alternative medicines and natural therapies to discover more effective anticancer agents with reduced side effects [6]. To address this challenge, plants and their biologically active compounds, known as phytochemicals, offer a promising avenue for cancer treatment with minimal adverse effects, concurrently enhancing the quality of human life [5]. Phyto chemicals enhance the quality of life in cancer patients by exerting antioxidant, anti-inflammatory and immunomodulatory effects, while also offering potential anticancer benefits and symptom relief, thus supporting overall well-being during treatment and recovery [7]. Currently, 50% of the approved drugs are derived from plants and their metabolites. Pharmaceutical companies are increasingly focused on plant secondary metabolites and their origins for developing novel medicines to treat various diseases [8]. Phytochemicals or phytonutrients are present in every part of the plant from roots to flowers, and play roles in the plant’s growth and development. These phytochemicals exhibit biological activity in humans by scavenging free radicals, which is beneficial in cancer treatment [5]. Scientific evidence indicates that regular consumption or inclusion of plant-based products in our daily diet can decrease the risk of various cancers [9]. Bioactive compounds from plants have shown significant anticancer activity in both in-vitro and in-vivo models by scavenging free radicals and inhibiting cancer cell proliferation [5]. Several naturally occurring plant-derived drugs approved by the FDA include paclitaxel, vincristine, vinblastine, etoposide, topotecan and irinotecan [10]. Additionally, a number of promising agents in preclinical and clinical trials include flavopiridol, roscovitine, silvesterol, betulinic acid and combretastatin A-4 [10]. More than 100 new natural products and their derivatives are currently in clinical development primarily targeting anticancer and antiinfective activities [11]. Repurposing FDA approved drugs from plant origins reduces the time, investment, cost and resources needed to develop new drug molecules while ensuring safety [12]. Preclinical and clinical safety data facilitate the development of potential lead molecules for specific diseases with reduced time, cost and lower market failure rates [5, 13]. In repurposing strategies, drug candidates are selected based on specificity, bioavailability, efficacy, safety, affordability, reduced chances of failure and low toxicity [14, 15].

The aim of this review is to explore synergistic strategies for cancer treatment, emphasizing the integration of natural products, drug repurposing, and molecular targeting approaches to enhance therapeutic efficacy and minimize adverse effects. Through comprehensive analysis, the review seeks to provide insights into innovative therapeutic combinations that hold promise for improving patient outcomes in cancer management.

2 Main text

2.1 Synthetic anticancer drugs and their adverse effects

Methotrexate is a chemotherapeutic drug commonly used to treat various cancers, autoimmune conditions and as an anti-inflammatory agent [16]. However, methotrexate has notable adverse side effects including oral ulcers, gastrointestinal bleeding, diarrhoea and osteopathy [17]. Another drug thioguanine commonly known as 6-thioguanine is used to treat chronic myeloid leukemia and lymphocytic leukemia. Thioguanine inhibits the aggressive nature of tumors in their early stages and can be easily permeate cancer cells. It interferes with nucleic acids, cleaving DNA molecules to enhance cell apoptosis [18]. While 6-thioguanine provides short-term relief, further studies are needed to analyze its long-term toxicity [19]. Side effects of 6-thioguanine include appetite loss, headache, and sore throat. In a previous clinical study on ninety cancer patients receiving chemotherapeutic drugs such as carboplatin, gemcitabine, paclitaxel, and doxorubicin, 83.3% experienced nausea and 78.9% experienced vomiting. These patients also reported depression, weakness, mouth dryness and appetite loss [20].

Thalidomide and lenalidomide are used as antineoplastic agents with immunomodulatory activity. Lenalidomide is commonly used for various cancer types[21]. However, it has adverse effects, including thrombocytopenia, neutropenia and venous thromboembolism [22]. Thalidomide known for its teratogenic properties can cause severe limb defects in fetuses when used as a sedative by pregnant woman [21]. Additionally, thalidomide has shown hepatotoxicity in patients at higher doses, resulting in acute liver failure [23]. Cyclophosphamide is used to treat various forms of cancer and severe autoimmune disorders. Its adverse effects include cardiotoxicity, secondary malignancies, embryo-fetal toxicity, hemorrhagic cystitis, and hepatotoxicity [24].

Chlorambucil, an alkylating agent is used to treat lymphocytic leukemia and occasionally autoimmune disorders. Its use has been associated with hypersensitive reactions, with adverse effects including Stevens-Johnson syndrome, neutropenia, necrolysis, thrombocytopenia, secondary malignancies and rare instance of liver damage [25]. Cisplatin is utilized for breast, colon and lung cancer with adverse effects such as teratogenicity, an increased risk of secondary malignancies, carcinogenicity, renal toxicity, nausea and mutagenicity [26]. Bleomycin used for treating germ cell and testicular cancer can cause hepatotoxicity. Other adverse effects include hypersensitivity, malignant hyperthermia, dizziness, alopecia and intestinal pneumonitis [27].

Doxorubicin, a cytotoxic anticancer agent is used for lymphomas, solid cancers and leukemia. High doses of doxorubicin can lead to severe cardiotoxicity and secondary malignancies [28]. 5-fluorouracil is employed to treat solid tumors such as breast, ovarian, pancreatic, liver and gastric cancers with adverse effects including hepatotoxicity and a distinctive syndrome in patients [29]. Cellular and molecular changes are common and vary significantly between different types of cancer. Phytochemical substitutes, high cancer prevalence, multiple tumor biopsies and inflammation leading to metastasis are significant challenges in developing alternative medicine due to their high heterogeneity [30]. Plant-based medicines and their phytochemicals are highly regarded for their potential benefits [31].

2.2 Phytochemicals and their biological activities

2.2.1 Phytochemicals as scavenging free radicals (antioxidant activity)

In biological systems, free radicals molecules with a very short half-life of less than 10–6 s. These radicals, characterized by an unpaired electron in their outer orbit are highly reactive with stable molecules, leading to imbalances in biological functions [32]. Although, the human body has antioxidant enzymes to neutralize and eliminate free radicals, the best way to mitigate their effects is by using phytochemicals found in plants and plant products [33]. Free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) can damage biomolecules leading to tissue injury [34]. While ROS are beneficial for certain cellular physiological functions, their excess can damage cell membranes and DNA. These radicals interact with DNA, causing oxidation, mutations, imbalances in membrane fluidity and lipid peroxidation [35].

Plants have long been a source of medicines for treating various human diseases [36]. Consequently, plant products have gained significant interest among researchers, who are investigating plant-based compounds for their antioxidant properties. Vegetables such as sweet potatoes, tomatoes, carrots, broccoli, spinach, cabbage, onions and beetroot are rich sources of phytochemicals that play a crucial role in scavenging free radicals [37]. Similarly, fruit consumption enhances the metabolic activity of the human body and reduces disease burden [38]. The various classes of phytochemicals include polyphenols, alkaloids, flavonoids, glycosides, tannins, saponins and triterpenes. Polyphenols and flavonoids in fruits and vegetables are particularly beneficial to human health [39]. These phenolic compounds and flavonoids are prominent groups of phytochemicals that significantly improve the quality of human life. Notably, phytochemicals with antioxidant potential include hydroxycinnamates, carotenoids, anthocyanidins, bioflavonoids, glutathione, butein, ellagitannins, epicatechin and curcumin[40].

2.2.2 Phytochemical’s role in inflammation

Inflammation is the body’s initial response to injury, whether ischemic or physical. During inflammation, immunological and biochemical reactions occur at the cellular level to help recover from the injury [41]. However, if the inflammatory response becomes chronic, inflammatory mediator markers, cytokines, and chemokine receptors can hinder recovery. Malfunctioning inflammation at the cellular and tissue levels can lead to uncontrolled cell division [42]. NF-κB is a key transcription factor responsible for the over expression of proinflammatory genes including interleukins and TNF-α [43]. Alterations in TNF-α, COX2 and interleukins can lead to chronic inflammation and subsequently cancer [44]. MAPK phosphorylation regulates the production of NO, proinflammatory genes and the activation of NF-κB [45]. Therefore, inhibiting or suppressing proinflammatory and inflammatory mediators are crucial molecular targets for treating diseases, such as cancer, cardiovascular diseases and diabetes [41].

Phytochemicals exert their effects by modulating multiple signaling pathways, including inflammatory pathways, metabolic pathways, apoptosis and cell signaling pathways [46]. Their anti-inflammatory activity which contributes to anticancer effects, involves the suppression of NF-κB activation, inflammatory cytokine production and down-regulation of COX-2 [47]. NF-κB serves as a key transcription factor in both inflammation and cancer, inducing the expression of genes associated with metastasis, angiogenesis, anti-apoptosis and cell proliferation [48]. In cell line studies, curcumin has been observed to inhibit NF-κB activation induced by tumor necrosis factor, interleukin, hydrogen peroxide and phorbol ester [49]. Phytochemicals like resveratrol and phytoalexins abundant in grape skin and red wine exhibit anti-inflammatory and antineoplastic activity [50]. Resveratrol’s inhibitory effects on tumor growth are attributed to its anti-inflammatory activity [51]. Additionally, resveratrol suppresses the expression of inflammatory enzymes such as iNOS and COX-2 in cancer cells by inhibiting the NF-κB activity [52, 53].

2.2.3 Phytochemicals as anticancer drugs

Phytochemicals and their derivatives found in various parts of the plants exhibit diverse pharmacological activities in the human body. Compounds such as phenolic compounds, tannins, glycosides, flavonoids, alkaloids, gums and resins possess anticancer properties [31]. Scientific evidence supports the significant anticancer potential of phytochemicals, with an estimated 50% of approved anticancer drugs being plant-derived compounds developed between 1940 and 2019 [54]. Natural drugs derived from plants, which are non-toxic and do not adversely affect normal cells, are valuable in drug discovery [55]. Despite the vast number of plant species, only a small fraction, approximately 10%, have been investigated for their pharmacological activities and therapeutic potential [56].

Phytochemicals exert their anticancer effects through various molecular targets and signal transduction pathways, including membrane bound receptors, kinases, transcriptional factors, downstream tumor activator or suppressor proteins, microRNAs, caspases and cyclins [56,57,58]. In the human body, phytochemicals contribute to reducing superoxide radicals (antioxidant activity), and decreasing VEGF, HIF-1α, bFGF, MMP, and endothelial cell proliferation (angiogenesis). They also decrease cell adhesion, invasion, cell proliferation and oncogenic expression [59]. Additionally, phytochemicals promote cell apoptosis, enhance tumor suppressor gene expression, induce cell cycle arrest, boost immune function and surveillance, and inhibit enzymes such as COX-2, histone deacetylase and trypsin [60].

The phytochemical compounds and their structures are represented in Fig. 1. Flavonol compounds such as quercetin and catechins exhibit inhibitory activity on tumor cells and cancer cell progression [61, 62]. Allicin (found in garlic) and sulforaphane are isothiocyanate compounds known for their anti-inflammatory and proapoptotic activity on cancer cells [63, 64]. Allicin regulates the STAT3 signaling pathway leading to the suppression of cancer cell progression [65]. Curcumin induces cell apoptosis, autophagy while down regulating the PI3K/AKT/mTOR/P70S6K pathway resulting in cell death [65]. Gingerol modulates cell signaling pathways associated with cancer, while resveratrol suppresses tumor cell proliferation [66, 67]. Andrographolide induces cell cycle arrest and cellular death by augmenting the intracellular reactive oxygen species (ROS) [68], where as paclitaxel suppresses cancer cell progression [68, 69]. Berberine an alkaloid affects cancer cell growth and metastasis [70]. Although, not clinically used for cancer treatment, colchicine affects the G2/M phase of the cell cycle leading to cell apoptosis [71]. Epigallocatechin functions as an antioxidant by modulating reactive oxygen species and NF-κB signaling pathways [72]. Withaferin, a natural compound acts as an antiproliferative agent by blocking the cyclins and the STAT3 pathway [73]. Other plant-derived compounds such as lycopene (carotenoids), cyanidin (anthocyanins), hesperitin(flavanone) and genistein (isoflavones) possess antioxidant potential and regulate cancer progression [5].

Fig. 1
figure 1

Chemical structures of phytochemical compounds from plants (Structures are redrawn using Chemdraw online software)

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The phytochemicals and their derivatives showed anticancer activity, and they are as follows:

2.2.3.1 Taxanes

Taxanes, known for their anti-tumor properties were initially discovered in the bark of the Yew tree (Taxus baccata). These compounds, including docetaxel and paclitaxel, are robust antitumor agents that function at a molecular level. Taxanes stabilize microtubules, leading to disruptions in cell division and cell cycle arrest [74]. The primary actions of taxanes include inducing programmed cell death, stabilizing microtubules, and causing mitotic arrest. Docetaxel specifically attenuates the expression of bcl-2 and bcl-xL genes, which are involved in cell survival [75]. Paclitaxel kills tumor cells by inducing multipolar divisions, resulting in the formation of two or three daughter cells that become aneuploid due to failed cytokinesis [76].

2.2.3.2 Berberine

Berberine is a bioactive compound isolated from the root and rhizome of Berberis vulgaris (barberry), Berberis aquifolium, Rhizoma coptidis and Tinospora cordifolia. [77]. It has been used to control the spread of cancers, such as breast, colorectal and prostate cancer [78]. Berberine induces programmed cell death, causes cell cycle arrest at the G2/M phase, inhibits anti-apoptotic proteins like Bcl-2 and c-IAP1, and activates pro-apoptotic proteins, such as p53, p21, caspase-3 and caspase-9 [79].

2.2.3.3 Camptothecins

Camptothecin is a quinolone bioactive compound isolated from chinese tree Camptotheca acuminata. Semi-synthetic derivatives of camptothecin, irinotecan and topotecan are currently approved drugs by the FDA. Irinotecan is prescribed for treating lung and colon cancers, either alone or in combination therapy [80]. Camptothecin and its derivatives inhibit the topoisomerase 1 enzyme leading to DNA damage and cell death [81].

2.2.3.4 Silymarin

Silymarin is a flavolignan extracted from Sylibum marianum. It comprises compounds like silychrystin, isosilybin, silydianin and silibinin [82]. These silymarin compounds arrest cyclin-dependent kinases, leading to cell cycle arrest and cell apoptosis. A combination of paclitaxel, silymarin and antibiotics is used to treat large intestine cancer [83].

2.2.3.5 Chalcone

Chalcone is an anti-tumor flavone found in edible greens and fruits. It is responsible for triggering various caspases and upregulating proapoptotic proteins, such as Bid, Bax, and Bak. Chalcones are used to treat liver, breast and adenocarcinoma cancers [84].

2.2.3.6 Colchicine

Colchicine is a natural bioactive compound is isolated from Colchicum autumnale (Colchicaceae) and used to treat inflammatory diseases like arthritis, gout, cirrhosis. Colchicine induces caspase-mediated cell death and targets tubulin, arresting the cell cycle at various phases [85]. Recently, plants like Gloriosa superba from tropical regions have become significant sources of colchicine [60].

2.3 Advantages of natural products over synthetic drugs

Natural products offer several advantages over synthetic drugs including greater chemical diversity, which enhances the likelihood of discovering novel therapeutic agents [86]. Additionally, natural products often possess complex molecular structures that interact with biological targets in a more nauanced and selective manner, potentially reducing off-target effects and toxicity [87] Furthermore, the evolutionary adaptation of plants and microorganisms has resulted in the production of bioactive compounds with optimized pharmacological properties such as improved bioavailability and biocompatibility [88]. In addition to this, natural products often exhibit synergistic effects when used in combination, offering enhanced therapeutic efficacy compared to single-agent synthetic drugs [89].

3 Repurposed drugs from phytochemical’s origin

The FDA approved non-oncological drugs could target both known and unknown vulnerabilities in the body [90]. Drugs of phytochemical origin have added benefits compared to synthetic drugs. Approximately 20% of cancers, such as stomach, pancreatic, colon and cervical cancers, can be restricted by including fruits in our regular diet [5] Phytochemicals are rich in flavonoids, alkaloids, phenols, antioxidants, vitamins, terpenoids and sesquiterpenes [91]. The critical parameters that need to be studied in drug repurposing include formulation, dosage, combination with other drugs, drug delivery, adverse effects, route of administration, molecular target, mechanism and safety [92] (Fig. 2). Identifying novel molecular targets and developing FDA approved non-oncological drugs is a critical strategy for cancer treatment.

Fig. 2
figure 2

Schematic representation of phytochemicals from medicinal plants and the repurposing of FDA approved phytochemicals for cancer treatment

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The advantages of phytochemicals as anticancer agents over synthetic drugs include reduced toxicity or no toxicity, nutrient richness, lack of side effects, efficacy, safety, availability of resources, direct anticancer mechanisms and prevention of chronic diseases [93, 94]. The non-oncological drugs derived from phytochemicals, their mechanisms of action, clinical trials and their treatment are listed in Tables 1, 2 and 3. Artemisinin, a sesquiterpene lactone produced by the Artemisia annua plant, is used as an antimalarial drug and has been employed for several years in Chinese medicine for treating chills and fever. This drug has low toxicity, and is safe and well tolerated in cancer treatment [95]. The artemisinin derivative artesunate is a potent drug molecule due to its hydrophilic group, which enhances its anticancer properties, including apoptosis induction, DNA damage and oxidative stress [96].

Table 1 Antimalarial and antibiotic-based drugs targeting various types of cancers and their clinical trials
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Table 2 Anti-inflammatory and cardiac based drugs targeting various types of cancers and their clinical trials
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Table 3 Antidiabetic and neuromuscular drugs targeting various types of cancers and their clinical trials
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Aspirin, a non-steroidal anti-inflammatory drug (NSAID) used for cardioprotection, has demonstrated anticancer activity by regulating transcriptional factors, signaling pathways and mitochondrial functions. Long-term use of aspirin has been associated with a reduced risk of various cancers [97]. Berberine an isoquinoline alkaloid acts as an anticancer agent by regulating the activation of proteins and gene expression involved in tumor processes [70]. Chloroquine, typically used as an antimalarial drug has been repurposed for cancer treatment due to its ability to inhibit the autophagy process [98]. Curcumin, a polyphenol pigment with anti-inflammatory properties, disrupts cell signal transduction pathways, inhibiting tumor proliferation and growth [99]. Digoxin, a cardiac glycoside used for congestive heart failure with atrial fibrillation suppresses tumors by inhibiting the Src oncogene involved in tumor formation [100].

Ginkgo biloba leaf extract possess anticancer properties due to its antiangiogenic effects and inhibition of carcinogen related processes [101]. Genistein, an isoflavone compound, demonstrates antineoplastic activity by inhibiting topoisomerase-II, inducing DNA fragmentation and causing G2/M cell cycle arrest [102]. Hypericin, an anthraquinone derivative acts as an anticancer agent by preventing the genotoxic effects of carcinogens [103]. Levofloxacin, a fluoroquinolone antibiotic, inhibits cancer cell proliferation and induces apoptosis. Metformin, an antidiabetic drug for type 2 diabetes, reduces cancer risk by modulating the mitochondrial electron transport chain complex 1 and mTORc1 [104]. Resveratrol, a phytoalexin inhibits tumor necrosis factor induced activation of NF-κB, thereby controlling tumor formation [105]. Tanshinone-II A, a diterpenoid derivative exhibits antitumor activity by inhibiting the Ras/MAPK signaling pathway [106].

4 Molecular targets and mechanism of action of non-oncological drugs

Phytochemical drug molecules exerts anticancer activity through various mechanisms (Fig. 3). They selectively inhibit the proliferation of rapidly dividing cancer cells, induce cell cycle arrest, promote apoptosis, regulate the immune system, inhibit angiogenesis and metastasis, remove oxidative stress and modulate growth factors [6, 117]. The molecular targets of FDA approved non-oncological drugs for various types of cancers have been extensively highlighted in the literature. This comprehensive understanding of their mechanisms highlights the potential of repurposing these phytochemicals for effective cancer treatments [118].

Fig. 3
figure 3

Schematic representation of anticancer mechanism of repurposed drugs. (1&2: Artemisinin and artesunate; 3: Aspirin; 4: Berberine; 5: Chloroquine; 6: Curcumin; 7: Digoxin; 8: Gingko biloba; 9: Genistein; 10: Hypericin; 11: Levofloxacin; 12: Metformin; 13: Resveratrol and 14: Tanshinone II A)

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Artemisinin and its derivatives, naturally occurring antimalarial drugs derived from plants, have demonstrated significant anticancer activity [95]. Artemisinin is a sesquiterpene lactone compound with a unique 1,2,4-trioxane ring system. Its potent anticancer affects are primarily due to the endoperoxide bond, which is activated by ferrous (Fe2+) ions leading to cytotoxic activity [119]. It induces apoptosis primarily through the generation of free radicals upon interaction with iron ions within the cell. These free radicals induce oxidative stress and damage cellular components, triggering apoptotic pathways that ultimately lead to cell death [120]. Additionally, artemisinin disrupts the normal progression of the cell cycle, by arresting it at the G1 phase. This prevents cancer cells from advancing into the S phase, where DNA synthesis occurs, thereby halting their proliferation [121]. These dual mechanisms highlight artemisinin potential as an anticancer agent by targeting both cell cycle regulation and apoptotic pathways in cancer cells [122].

Aspirin acta as an anti-inflammatory by inhibiting NF-κB activation through blockade of IkB α phosphorylation. This prevents the degradation of IkB α, thereby sequestering NF-κB in the cytoplasm and preventing its translocation to the nucleus [123]. By reducing NF-κB mediated transcription of proinflammatory genes, aspirin decreases the production of cytokines, and other inflammatory mediators, thereby exerting its anti-inflammatory effects. This mechanism is pivotal in its therapeutic use for managing inflammation and potentially influencing pathways related to cancer [124]. Berberine, an alkaloid inhibits bcl-2 expression by activating caspase-3. This activation along with cytochrome c release enhances AMPK activity and increases ROS production, promoting apoptosis and controlling cancer progression [125]. Lys05, a dimeric form of chloroquine, functions as an effective anticancer agent through several mechanisms. It accumulates within lysosomes, where it disrupts their acidic environment. This alkalization interferes with lysosomal function, leading to impaired autophagy, a cellular process crucial for recycling and survival of cancer cells under stress [126]. By inhibiting autophagy, Lys05 promotes cell death pathways in cancer cells. This dual action of lysosomal alkalization and autophagy inhibition underscores its potential as a therapeutic strategy against cancer, particularly in targeting resistant or adaptive tumor cells [127].

Curcumin exhibits potent anticancer effects by down-regulating AKT expression in MDA-MB-231 cells, thereby inhibiting cell proliferation. Additionally, curcumin suppresses the mTORC1 pathway, which is crucial for cell proliferation, survival and angiogenesis blockade [128]. Digoxin interferes with the activation and downstream signaling of SRC kinase. SRC is a non-receptor tyrosine kinase involved in various signaling pathways that regulate cell growth, differentiation, and survival. By inhibiting SRC, digoxin disrupts these pathways, which are crucial for cancer cell proliferation and progression [100]. Bioflavonoids derived from Ginkgo biloba flowers demonstrate in-vitro anticancer activity across various cell lines by arresting the G2/M phase of the cell cycle. They induce apoptosis through activation of proapoptotic proteins such as caspase-3 and Bax. Notably, bilobetin, a bioflavonoid inhibits Bcl-2, an anti-apoptotic protein, thereby exerting antiproliferative effects [129].

Hypericin, derived from Hypericum perforatum, acts as an anthraquinone derivative that modulates the ERK1/2 (extracellular signal-regulated kinase) cascade. It also partially inhibits the STAT-1 and NF-κB signaling pathways contributing to its potential as an anticancer agent [130]. Levofloxacin, an antibiotic, deactivates the PI3K/Akt/mTOR pathway, thereby inhibiting mitochondrial biogenesis and potentially impacting cancer survival [111]. Metformin exerts its anticancer effects by inhibiting mTOR activity within the PI3K/Akt/mTOR signaling pathway, which is crucial for cell proliferation [131]. Reservatrol inhibits MMP-9 expression, cyclooxygenase-2, and anti-apoptotic proteins like Bcl-2, Bcl-Xl, and TRAF1. It also suppresses the NF-κB signaling pathway through inhibition of IkB-α kinase [132]. Tanshinone II A has been shown to inhibit cell proliferation and down-regulates STAT 3 in gastric cell lines, thereby suppressing tumor growth [116].

5 Why non-oncological natural products possessing anticancer potential

Chemotherapy remains a primary treatment for cancer despite its significant toxicity and potential fatal adverse effects for patients [133]. Natural products, akin to chemotherapeutic agents have demonstrated promising anti-tumor and antimetastatic potential in preclinical trials [134]. Artemisinin’s endoperoxide bond is crucial for both its antimalarial and anticancer properties with derivatives like artesunate also showing anticancer activity due to this moiety. Aspirin’s acetyl group is key to its anti-inflammatory and anticancer activities [97]. Quaternary berberine-12-N,N-di-n-alkylamine chloride exhibits potent anticancer effects [135]. Curcumin’s, benzyl rings contribute significantly to its ability to inhibit tumor growth [65]. Digoxin’s saccharide moiety present at the C-3 position of its steroid core structure plays a pivotal role in its anticancer activity [136]. Genistein, an isoflavone with an aromatic substitution at the C-2 position, shows broad bioactivity against diseases including cancer [102]. Hypericin’s, delocalized π-electron system within its aromatic ring contributes to its anticancer potential [137]. Metformins extensive π-bond interactions with copper are responsible for its anticancer activity [138]. Levofloxacins fused ring system bridging between C-8 and N-1, exhibits bioactivity against cancer cells [104]. Resveratrol, a phytoestrogen is predominantly found in trans-form, which along with its glucoside demonstrates diverse biological activities including anticancer potential [132]. Tanshinone compounds down-regulate STAT-3 phosphorylation and exert a broad spectrum of antitumor functions [106].

6 Synergistic effects of various phytochemicals

Curcumin from turmeric and genistein from soy have demonstrated synergistic effects in inhibiting the growth of breast cancer cells. Together, they enhance apoptosis induction and reduce cancer cell proliferation more effectively than when used individually [139]. Similarly, curcumin and berberine work synergistically to inhibit cancer cell proliferation and induce apoptosis, particularly in colorectal cancer, by modulating signaling pathways involved in cancer growth and survival [140]. Aspirin, in combination with curcumin inhibits cancer cell proliferation by modulating inflammatory pathways and inducing apoptosis [141]. Furthermore, aspirin paired with resveratrol reduces cancer cell viability and tumor growth especially in breast and colorectal cancer models [142]. Aspirin combined with the flavonoid quercetin enhances apoptosis and reduces inflammation in colorectal cancer leading to the inhibition of cancer cell growth [143]. Quercetin when used with sulforaphane has been shown to reduce tumor growth and enhance apoptotic response in various cancer models [144].

Resveratrol, found in grapes possess strong antioxidant and anti-inflammatory properties when combined with quercetin, resveratrol suppresses cancer cell proliferation and promotes cell death [145]. Digoxin, a well known cardiac glycoside combined with metformin, an anti-diabetic drug, enhances anticancer effects by activating AMP-activated protein kinases (AMPK) and inhibiting the mTOR pathway [146]. These combinations represent a promising avenue for developing more effective and comprehensive cancer treatments [147]. Such synergistic approaches not only enhance anticancer activity but also reduce resistance and potentially lower the necessary dosage of each drug, thereby minimizing side effects [148]. This strategy highlights the potential of combining natural products with conventional drugs to achieve better therapeutic outcomes and improve patient quality of life [149].

7 Conclusion & future perspectives

In conclusion, leveraging synergistic strategies for cancer treatment by integrating natural products, drug repurposing, and precise molecular targeting offers a promising approach to enhancing therapeutic efficacy and minimizing adverse effects. This integrated therapy harnesses the unique properties of phytochemicals to work in tandem with repurposed drugs, targeting multiple pathways involved in cancer progression. By combining these elements, we can potentially overcome resistance mechanisms, improve patient outcomes, and pave the way for more personalized and effective cancer treatments. Continued research in this multidisciplinary field is essential to unlock the full potential of these synergistic strategies, ultimately leading to more holistic and successful cancer therapies.

Availability of data and materials

Not applicable.

Abbreviations

FDA:

Food and drug administration

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

NF-κB:

Nuclear factor kappa B

TNF-α:

Tumor necrosis factor α

COX-2:

Cyclooxygenase-2

MAPK:

Mitogen activated protein kinase

NO:

Nitric oxide

iNOS:

Inducible nitric oxide synthase

VEGF:

Vascular endothelial growth factor

HRF-1α:

Hypoxia induced factor 1α

bFGF:

Basic fibroblast growth factor

MMP:

Matrix metalloproteinases

PI3K:

Phosphoinositide 3-kinase

AKT:

Protein kinase B

mTOR:

Mammalian target of rapamycin 1

P70S6K:

P70 ribosomal S6 kinase

STAT3:

Signal transducer and activator of transcription 3

Bcl-2:

B-cell leukemia/lymphoma 2 protein

NSAID:

Non steroid anti-inflammatory drugs

RAT:

Rat islet cell line

References

  1. Wang Z, Fan Z, Yang L, Liu L, Sheng C, Song F, Chen K (2023) Higher risk of cardiovascular mortality than cancer mortality among long-term cancer survivors. Front Cardiovasc Med 10:1014400. https://doi.org/10.3389/fcvm.2023.1014400

    Article  PubMed  PubMed Central  Google Scholar 

  2. Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, de la Lastra JMP (2023) Cancer chemotherapy and beyond: current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis 10(4):1367–1401. https://doi.org/10.1016/j.gendis.2022.02.007

    Article  CAS  PubMed  Google Scholar 

  3. Hibino S, Kawazoe T, Kasahara H, Itoh S, Ishimoto T, Sakata-Yanagimoto M, Taniguchi K (2021) Inflammation-induced tumorigenesis and metastasis. Int J Mol Sci 22(11):5421. https://doi.org/10.3390/molecules27175436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Greten FR, Grivennikov SI (2019) Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51(1):27–41. https://doi.org/10.1016/j.immuni.2019.06.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Choudhari AS, Pallavi CM, Deshpande M, Prabhakar R, Prakash O (2020) Phytochemicals in cancer treatment: from preclinical studies to clinical practice. Front Pharmacol 10:16–14. https://doi.org/10.3389/fphar.2019.01614

    Article  CAS  Google Scholar 

  6. Anwar S, Almatroudi A, Alsahli MA, Khan MA, Khan AA, Rahmani AH (2020) Natural products: implication in cancer prevention and treatment through modulating various biological activities. Anticancer Agents Med Chem 20(17):2025–2040. https://doi.org/10.2174/1871520620666200705220307

    Article  CAS  PubMed  Google Scholar 

  7. Lee J, Han Y, Wang W, Jo H, Kim H, Kim S, Song YS (2021) Phytochemicals in cancer immune checkpoint inhibitor therapy. Biomolecules 11(8):1107. https://doi.org/10.3390/biom11081107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bhuiyan FR, Howlader S, Raihan T, Hasan M (2020) Plants metabolites: possibility of natural therapeutics against the COVID-19 pandemic. Front Med 7:444. https://doi.org/10.3389/fmed.2020.00444

    Article  Google Scholar 

  9. Nagy S, Petrosky SN, Beckler MD, Kesselman MM (2023) The impact of modern dietary practices on cancer risk and progression: a systematic review. Cureus. https://doi.org/10.7759/cureus.46639

    Article  PubMed  PubMed Central  Google Scholar 

  10. El-Seedi HR, Yosri N, Khalifa SA, Guo Z, Musharraf SG, Xiao J, Verpoorte R (2021) Exploring natural products-based cancer therapeutics derived from egyptian flora. J Ethnopharmacol 269:113626. https://doi.org/10.1016/j.jep.2020.113626

    Article  CAS  PubMed  Google Scholar 

  11. El-Seedi HR, Khalifa SA, Yosri N, Khatib A, Chen L, Saeed A, Verpoorte R (2019) Plants mentioned in the Islamic scriptures (Holy Qur’ân and Ahadith): traditional uses and medicinal importance in contemporary times. J Ethnopharmacol 243:112007. https://doi.org/10.1016/j.jep.2019.112007

    Article  CAS  PubMed  Google Scholar 

  12. Madigan M, Karhu E (2018) The role of plant-based nutrition in cancer prevention. J Unexplored Med Data 3:9. https://doi.org/10.20517/2572-8180.2018.05

    Article  Google Scholar 

  13. Rudrapal M, Khairnar JS, Jadhav GA (2020) Drug repurposing (DR): an emerging approach in drug discovery. Drug Repurposing Hypothesis Mol Asp Ther Appl. https://doi.org/10.5772/intechopen.93193

    Article  Google Scholar 

  14. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58. https://doi.org/10.1038/nrd.2018.168

    Article  CAS  PubMed  Google Scholar 

  15. Hernandez JJ, Pryszlak M, Smith L, Yanchus C, Kurji N, Shahani VM, Molinski SV (2017) Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front Oncol 7:273. https://doi.org/10.3389/fonc.2017.00273

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ren J, Fang Z, Yao L, Dahmani FZ, Yin L, Zhou J, Yao J (2015) A Micelle-like structure of poloxamer-methotrexate conjugates as nano carrier for methotrexate delivery. Int J Pharm 487(1–2):177–186. https://doi.org/10.1016/j.ijpharm.2015.04.014

    Article  CAS  PubMed  Google Scholar 

  17. Hamed KM, Dighriri IM, Baomar AF, Alharthy BT, Alenazi FE, Alali GH, Alzahrani S (2022) Overview of methotrexate toxicity: a comprehensive literature review. Cureus. https://doi.org/10.7759/cureus.29518

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bayoumy AB, Simsek M, Seinen ML, Mulder CJ, Ansari A, Peters GJ, De Boer NK (2020) The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol 16(2):111–123. https://doi.org/10.1080/17425255.2020.1719996

    Article  CAS  PubMed  Google Scholar 

  19. Zhang D, An X, Li Q, Man X, Chu M, Li H, Li Z (2020) Thioguanine induces apoptosis in triple-negative breast cancer by regulating PI3K–AKT pathway. Front Oncol 10:524922. https://doi.org/10.3389/fonc.2020.524922

    Article  PubMed  PubMed Central  Google Scholar 

  20. Stanslas J (2019) Cancer incidence and chemotherapy-induced adverse effects in Asia. Int J Care Sch. https://doi.org/10.31436/ijcs.v2i1.102

    Article  Google Scholar 

  21. Holstein SA, McCarthy PL (2017) Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience. Drugs 77:505–520. https://doi.org/10.1007/s40265-017-0689-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nadeem O, Ailawadhi S, Khouri J, Williams L, Catamero D, Maples K, Berdeja J (2024) Management of adverse events associated with pomalidomide-based combinations in patients with relapsed/refractory multiple myeloma. Cancers 16(5):1023. https://doi.org/10.3390/cancers16051023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ricart AD (2017) Drug-induced liver injury in oncology. Ann Oncol 28(8):2013–2020. https://doi.org/10.1093/annonc/mdx158

    Article  CAS  PubMed  Google Scholar 

  24. Subramanian R, Pathak H, Ravindran V (2019) Safety of cyclophosphamide therapy in autoimmune rheumatic diseases. Indian J Rheumatol 14(2):127–135. https://doi.org/10.4103/injr.injr_28_19

    Article  Google Scholar 

  25. Gomes LC, Ferrao ALM, Evangelista FCG, de Almeida TD, Barbosa RC, das Graças Carvalho M, de Paula-Sabino A (2018) Advances in chronic lymphocytic leukemia pharmacotherapy. Biomed Pharmacother 97:349–358. https://doi.org/10.1016/j.biopha.2017.10.105

    Article  CAS  PubMed  Google Scholar 

  26. Manavi MA, Fathian Nasab MH, Mohammad Jafari R, Dehpour AR (2023) Mechanisms underlying dose-limiting toxicities of conventional chemotherapeutic agents. J Chemother. https://doi.org/10.1080/1120009X.2023.2300217

    Article  Google Scholar 

  27. Moradi M, Hashemian MA, Faramarzi A, Goodarzi N, Hashemian AH, Cheraghi H, Jalili C (2024) Therapeutic effect of sodium alginate on bleomycin, etoposide and cisplatin (BEP)-induced reproductive toxicity by inhibiting nitro-oxidative stress, inflammation and apoptosis. Sci Rep 14(1):1565. https://doi.org/10.1038/s41598-024-52010-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kciuk M, Gielecińska A, Mujwar S, Kołat D, Kałuzińska-Kołat Ż, Celik I, Kontek R (2023) Doxorubicin—an agent with multiple mechanisms of anticancer activity. Cells 12(4):659. https://doi.org/10.3390/cells12040659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alessandrino F, Qin L, Cruz G, Sahu S, Rosenthal MH, Meyerhardt JA, Shinagare AB (2019) 5-Fluorouracil induced liver toxicity in patients with colorectal cancer: role of computed tomography texture analysis as a potential biomarker. Abdom Radiol 44(9):3099–3106. https://doi.org/10.1007/s00261-019-02110-3

    Article  Google Scholar 

  30. George BP, Chandran R, Abrahamse H (2021) Role of phytochemicals in cancer chemoprevention: insights. Antioxidants 10(9):1455. https://doi.org/10.3390/antiox10091455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar A, Nirmal P, Kumar M, Jose A, Tomer V, Oz E, Oz F (2023) Major phytochemicals: recent advances in health benefits and extraction method. Molecules 28(2):887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martemucci G, Costagliola C, Mariano M, D’andrea L, Napolitano P, D’Alessandro AG (2022) Free radical properties, source and targets, antioxidant consumption and health. Oxygen 2(2):48–78. https://doi.org/10.3390/oxygen2020006

    Article  CAS  Google Scholar 

  33. Suluvoy JK, Grace VB (2017) Phytochemical profile and free radical nitric oxide (NO) scavenging activity of Averrhoa bilimbi L. fruit extract. 3 Biotech 7(1):85. https://doi.org/10.1007/s13205-017-0678-9

    Article  PubMed  PubMed Central  Google Scholar 

  34. Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30:11–26. https://doi.org/10.1007/s12291-014-0446-0

    Article  CAS  PubMed  Google Scholar 

  35. Juan CA, Perez de la Lastra JM, Plou FJ, Perez-Lebena E (2021) The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int J Mol Sci 22(9):4642. https://doi.org/10.3390/ijms22094642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Altemimi A, Lakhssassi N, Baharlouei A, Watson DG, Lightfoot DA (2017) Phytochemicals: extraction, isolation, and identification of bioactive compounds from plant extracts. Plants 6(4):42. https://doi.org/10.3390/plants6040042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Adeyanju AA, Oyenihi OR, Oguntibeju OO (2021) Antioxidant-rich vegetables: impact on human health. Veg Crops-Health Benefits Cultiv. https://doi.org/10.5772/intechopen.101126

    Article  Google Scholar 

  38. Papaioannou KG, Kadi F, Nilsson A (2022) Benefits of fruit and vegetable consumption on prevalence of metabolic syndrome are independent of physical activity behaviors in older adults. Nutrients 14(2):263. https://doi.org/10.3390/nu14020263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Agidew MG (2022) Phytochemical analysis of some selected traditional medicinal plants in Ethiopia. Bull Natl Res Centre 46(1):87. https://doi.org/10.1186/s42269-022-00770-8

    Article  Google Scholar 

  40. Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A (2018) Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: an overview. Medicines 5(3):93. https://doi.org/10.3390/medicines5030093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Zhao L (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9(6):7204. https://doi.org/10.18632/oncotarget.23208

    Article  PubMed  Google Scholar 

  42. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y (2021) Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther 6(1):263. https://doi.org/10.1038/s41392-021-00658-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu T, Zhang L, Joo D, Sun SC (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2(1):1–9. https://doi.org/10.1038/sigtrans.2017.23

    Article  CAS  Google Scholar 

  44. Suluvoy JK, Sakthivel KM, Guruvayoorappan C, Grace VB (2017) Protective effect of Averrhoa bilimbi L. fruit extract on ulcerative colitis in wistar rats via regulation of inflammatory mediators and cytokines. Biomed Pharmacother 91:1113–1121. https://doi.org/10.1016/j.biopha.2017.05.057

    Article  PubMed  Google Scholar 

  45. Moeller T, Wolfheimer S, Goretzki A, Scheurer S, Schülke S (2019) NFκB-and MAP-kinase signaling contribute to the activation of murine myeloid dendritic cells by a Flagellin A: allergen fusion protein. Cells 8(4):355. https://doi.org/10.3390/cells8040355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ahmed MB, Islam SU, Alghamdi AA, Kamran M, Ahsan H, Lee YS (2022) Phytochemicals as chemo-preventive agents and signaling molecule modulators: current role in cancer therapeutics and inflammation. Int J Mol Sci 23(24):15765. https://doi.org/10.3390/ijms232415765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Guan C, Zhou X, Li H, Ma X, Zhuang J (2022) NF-κB inhibitors gifted by nature: the anticancer promise of polyphenol compounds. Biomed Pharmacother 156:113951. https://doi.org/10.1016/j.biopha.2022.113951

    Article  CAS  PubMed  Google Scholar 

  48. Pavitra E, Kancharla J, Gupta VK, Prasad K, Sung JY, Kim J, Tej MB, Choi R, Lee JH, Han YK, Raju GS (2023) The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy. Biomed Pharmacother 163:114822. https://doi.org/10.1016/j.biopha.2023.114822

    Article  CAS  PubMed  Google Scholar 

  49. Paul S, Sa G (2021) Curcumin as an adjuvant to cancer immunotherapy. Front Oncol 11:675923. https://doi.org/10.3389/fonc.2021.675923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fatima N, Baqri SSR, Alsulimani A, Fagoonee S, Slama P, Kesari KK, Haque S (2021) Phytochemicals from Indian ethnomedicines: promising prospects for the management of oxidative stress and cancer. Antioxidants 10(10):1606. https://doi.org/10.3390/antiox10101606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kursvietiene L, Kopustinskiene DM, Staneviciene I, Mongirdiene A, Kubová K, Masteikova R, Bernatoniene J (2023) Anti-cancer properties of resveratrol: a focus on its impact on mitochondrial functions. Antioxidants 12(12):2056. https://doi.org/10.3390/antiox12122056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J (2021) Anti-inflammatory action and mechanisms of resveratrol. Molecules 26(1):229. https://doi.org/10.3390/molecules26010229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Honari M, Shafabakhsh R, Reiter RJ, Mirzaei H, Asemi Z (2019) Resveratrol is a promising agent for colorectal cancer prevention and treatment: focus on molecular mechanisms. Cancer Cell Int 19(1):1–8. https://doi.org/10.1186/s12935-019-0906-y

    Article  CAS  Google Scholar 

  54. Sukhdev S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1667. https://doi.org/10.3389/fpls.2016.01667

    Article  Google Scholar 

  55. Nasim N, Sandeep IS, Mohanty S (2022) Plant-derived natural products for drug discovery: current approaches and prospects. The Nucleus 65(3):399–411. https://doi.org/10.1007/s13237-022-00405-3

    Article  PubMed  PubMed Central  Google Scholar 

  56. Dou J, Wang Z, Ma L, Peng B, Mao K, Li C, Su M, Zhou C, Peng G (2018) Baicalein and baicalin inhibit colon cancer using two distinct fashions of apoptosis and senescence. Oncotarget 9(28):20089–20102. https://doi.org/10.18632/oncotarget.24015

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zhang B, Fan X, Wang Z, Zhu W, Li J (2017) Alpinumisoflavone radiosensitizes esophageal squamous cell carcinoma through inducing apoptosis and cell cycle arrest. Biomed Pharmacother 95:199–206. https://doi.org/10.1016/j.biopha.2017.08.048

    Article  CAS  PubMed  Google Scholar 

  58. Yan XB, Xie T, Wang SD, Wang Z, Li HY, Ye ZM (2018) Apigenin inhibits proliferation of human chondrosarcoma cells via cell cycle arrest and mitochondrial apoptosis induced by ROS generation-an in vitro and in vivo study. Int J Clin Exp Med 11(3):1615–1631

    Google Scholar 

  59. Chaudhary P, Janmeda P, Docea AO, Yeskaliyeva B, Abdull Razis AF, Modu B, Sharifi-Rad J (2023) Oxidative stress, free radicals and antioxidants: Potential crosstalk in the pathophysiology of human diseases. Front Chem 11:1158198. https://doi.org/10.3389/fchem.2023.1158198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xie S, Zhou J (2017) Harnessing plant biodiversity for the discovery of novel anticancer drugs targeting microtubules. Front Plant Sci 8:720. https://doi.org/10.3389/fpls.2017.00720

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rauf A, Imran M, Khan IA, ur-Rehman M, Gilani SA, Mehmood Z, Mubarak MS (2018) Anticancer potential of quercetin: a comprehensive review. Phytother Res 32(11):2109–2130. https://doi.org/10.1002/ptr.6155

    Article  CAS  PubMed  Google Scholar 

  62. Cheng Z, Zhang Z, Han Y, Wang J, Wang Y, Chen X, Shao Y, Cheng Y, Zhou W, Lu X, Wu Z (2020) A review on anti-cancer effect of green tea catechins. J Funct Foods 74:104172. https://doi.org/10.1016/j.jff.2020.104172

    Article  CAS  Google Scholar 

  63. Bayat Mokhtari R, Baluch N, Homayouni TS, Morgatskaya E, Kumar S, Kazemi P, Yeger H (2018) The role of sulforaphane in cancer chemoprevention and health benefits: a mini-review. J Cell Commun Signal 12:91–101. https://doi.org/10.1007/s12079-017-0401-y

    Article  PubMed  Google Scholar 

  64. Zhang Y, Liu X, Ruan J, Zhuang X, Zhang X, Li Z (2020) Phytochemicals of garlic: promising candidates for cancer therapy. Biomed Pharmacother 123:109730. https://doi.org/10.1016/j.biopha.2019.109730

    Article  PubMed  Google Scholar 

  65. Tomeh MA, Hadianamrei R, Zhao X (2019) A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci 20(5):1033. https://doi.org/10.3390/ijms20051033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nafees S, Zafaryab M, Mehdi SH, Zia B, Rizvi MA, Khan MA (2021) Anti-cancer effect of gingerol in cancer prevention and treatment. Anticancer Agents Med Chem 21(4):428–432. https://doi.org/10.2174/1871520620666200918100833

    Article  CAS  PubMed  Google Scholar 

  67. Varoni EM, Lo Faro AF, Sharifi-Rad J, Iriti M (2016) Anticancer molecular mechanisms of resveratrol. Front Nutr 3:8. https://doi.org/10.3389/fnut.2016.00008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Khan I, Khan F, Farooqui A, Ansari IA (2018) Andrographolide exhibits anticancer potential against human colon cancer cells by inducing cell cycle arrest and programmed cell death via augmentation of intracellular reactive oxygen species level. Nutr Cancer 70(5):787–803. https://doi.org/10.1080/01635581.2018

    Article  CAS  PubMed  Google Scholar 

  69. Zhu L, Chen L (2019) Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett 24(1):1–11. https://doi.org/10.1186/s11658-019-0164-y

    Article  Google Scholar 

  70. Habtemariam S (2020) Recent advances in berberine inspired anticancer approaches: from drug combination to novel formulation technology and derivatization. Molecules 25(6):1426. https://doi.org/10.3390/molecules25061426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kumar A, Sharma PR, Mondhe DM (2017) Potential anticancer role of colchicine-based derivatives: an overview. Anticancer Drugs 28(3):250–262. https://doi.org/10.1097/CAD.0000000000000464

    Article  CAS  PubMed  Google Scholar 

  72. Mokra D, Joskova M, Mokry J (2022) Therapeutic effects of green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in relation to molecular pathways controlling inflammation, oxidative stress, and apoptosis. Int J Mol Sci 24(1):340. https://doi.org/10.3390/ijms24010340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee IC, Choi BY (2016) Withaferin-A—a natural anticancer agent with pleitropic mechanisms of action. Int J Mol Sci 17(3):290. https://doi.org/10.3390/ijms17030290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ojima I, Lichtenthal B, Lee S, Wang C, Wang X (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26(1):1–20. https://doi.org/10.1517/13543776.2016.1111872

    Article  CAS  PubMed  Google Scholar 

  75. Ogura T, Tanaka Y, Tamaki H, Harada M (2016) Docetaxel induces Bcl-2-and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells. Int J Oncol 48(6):2330–2338. https://doi.org/10.3892/ijo.2016.3482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Scribano CM, Wan J, Esbona K, Tucker JB, Lasek A, Zhou AS, Weaver BA (2021) Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel. Sci Transl Med 13(610):eabd4811. https://doi.org/10.1126/scitranslmed.abd4811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Neag MA, Mocan A, Echeverría J, Pop RM, Bocsan CI, Crisan G, Buzoianu AD (2018) Berberine: Botanical occurrence, traditional uses, extraction methods, and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol 9:557. https://doi.org/10.3389/fphar.2018.00557

    Article  PubMed  PubMed Central  Google Scholar 

  78. Barzegar E, Fouladdel S, Movahhed TK, Atashpour S, Ghahremani MH, Ostad SN, Azizi E (2015) Effects of berberine on proliferation, cell cycle distribution and apoptosis of human breast cancer T47D and MCF7 cell lines. Iran J Basic Med Sci 18(4):334

    PubMed  PubMed Central  Google Scholar 

  79. Och A, Podgórski R, Nowak R (2020) Biological activity of berberine—a summary update. Toxins 12(11):713. https://doi.org/10.3390/toxins12110713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li F, Jiang T, Li Q, Ling X (2017) Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: Did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am J Cancer Res 7(12):2350

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Wen Y, Wang Y, Liu X, Zhang W, Xiong X, Han Z, Liang X (2017) Camptothecin-based nanodrug delivery systems. Cancer Biol Med 14(4):363. https://doi.org/10.20892/j.issn.2095-3941.2017.0099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Koltai T, Fliegel L (2022) Role of silymarin in cancer treatment: facts, hypotheses, and questions. J Evid-Based Integr Med 27:2515690X211068826. https://doi.org/10.1177/2515690X211068826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Delmas D, Xiao J, Vejux A, Aires V (2020) Silymarin and cancer: a dual strategy in both in chemoprevention and chemosensitivity. Molecules 25(9):2009. https://doi.org/10.3390/molecules25092009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Das M, Manna K (2016) Chalcone scaffold in anticancer armamentarium: a molecular insight. J Toxicol 76(51):42–47. https://doi.org/10.1155/2016/7651047

    Article  CAS  Google Scholar 

  85. Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL (2018) Colchicine: an ancient drug with novel applications. Br J Dermatol 178(2):350–356. https://doi.org/10.1111/bjd.15896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mushtaq S, Abbasi BH, Uzair B, Abbasi R (2018) Natural products as reservoirs of novel therapeutic agents. Excli J 17:420–451. https://doi.org/10.17179/excli2018-1174

    Article  PubMed  PubMed Central  Google Scholar 

  87. Dzobo K (2022) The role of natural products as sources of therapeutic agents for innovative drug discovery. Compr Pharmacol. https://doi.org/10.1016/B978-0-12-820472-6.00041-4

    Article  Google Scholar 

  88. Chaachouay N, Zidane L (2024) Plant-derived natural products: a source for drug discovery and development. Drugs Drug Candidates 3(1):184–207. https://doi.org/10.3390/ddc3010011

    Article  Google Scholar 

  89. Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K (2018) Natural products for drug discovery in the 21st century: innovations for novel drug discovery. Int J Mol Sci 19(6):1578. https://doi.org/10.3390/ijms19061578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, Huang C (2020) Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther 5(1):113. https://doi.org/10.1038/s41392-020-00213-8

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tinoush B, Shirdel I, Wink M (2020) Phytochemicals: potential lead molecules for MDR reversal. Front Pharmacol 11:832. https://doi.org/10.3389/fphar.2020.00832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hua Y, Dai X, Xu Y, Xing, Liu H, Lu T, Zhang Y (2022) Drug repositioning: progress and challenges in drug discovery for various diseases. Eur J Med Chem 234:114239. https://doi.org/10.1016/j.ejmech.2022.114239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Naylor DM, Kauppi DM, Schonfeld JM (2015) Therapeutic drug repurposing, repositioning and rescue. Drug Discov 57

  94. Ranjan A, Ramachandran S, Gupta N, Kaushik I, Wright S, Srivastava S, Das H, Srivastava S, Prasad S, Srivastava SK (2019) Role of phytochemicals in cancer prevention. Int J Mol Sci 20(20):4981. https://doi.org/10.3390/ijms20204981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang Y, Xu G, Zhang S, Wang D, Saravana Prabha P, Zuo Z (2018) Antitumor research on artemisinin and its bioactive derivatives. Nat Products Bioprospecting 8:303–319. https://doi.org/10.1007/s13659-018-0162-1

    Article  CAS  Google Scholar 

  96. Khanal P (2021) Antimalarial and anticancer properties of artesunate and other artemisinins: current development. Monatshefte für Chemie-Chem Mon. https://doi.org/10.1007/s00706-021-02759-x

    Article  Google Scholar 

  97. Sankaranarayanan R, Kumar DR, Altinoz MA, Bhat GJ (2020) Mechanisms of colorectal cancer prevention by aspirin—a literature review and perspective on the role of COX-dependent and-independent pathways. Int J Mol Sci 21(23):9018. https://doi.org/10.3390/ijms21239018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhou W, Wang H, Yang Y, Chen ZS, Zou C, Zhang J (2020) Chloroquine against malaria, cancers and viral diseases. Drug Discov Today 25(11):2012–2022. https://doi.org/10.1016/j.drudis.2020.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Giordano A, Tommonaro G (2019) Curcumin and cancer. Nutrients 11(10):2376. https://doi.org/10.3390/nu11102376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lin SY, Chang HH, Lai YH, Lin CH, Chen MH, Chang GC, Tsai MF, Chen JJ (2015) Digoxin suppresses tumor malignancy through inhibiting multiple Src-related signaling pathways in non-small cell lung cancer. PLoS ONE 10(5):e0123305. https://doi.org/10.1371/journal.pone.0123305

    Article  PubMed  PubMed Central  Google Scholar 

  101. Chen P, Wang T, Chen Q (2023) Ginkgo biloba golden leaf extract (GGLE) inhibits melanoma cell invasion and angiogenesis through inhibition of angiogenin. Integr Cancer Ther 22:15347354221134512. https://doi.org/10.1177/1534735422113451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tuli HS, Tuorkey MJ, Thakral F, Sak K, Kumar M, Sharma AK, Sharma U, Jain A, Aggarwal V, Bishayee A (2019) Molecular mechanisms of action of genistein in cancer: recent advances. Front Pharmacol 10:1336. https://doi.org/10.3389/fphar.2019.01336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Jendzelovska Z, Jendzelovsky R, Kucharova B, Fedorocko P (2016) Hypericin in the light and in the dark: two sides of the same coin. Front Plant Sci 7:560. https://doi.org/10.3389/fpls.2016.00560

    Article  PubMed  PubMed Central  Google Scholar 

  104. Song M, Wu H, Wu S, Ge T, Wang G, Zhou Y, Sheng S, Jiang J (2016) Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage. Biomed Pharmacother 84:1137–1143. https://doi.org/10.1016/j.biopha.2016.10.034

    Article  CAS  PubMed  Google Scholar 

  105. Jiang Z, Chen K, Cheng L, Yan B, Qian W, Cao J, Yang W (2017) Resveratrol and cancer treatment: updates. Ann N Y Acad Sci 1403(1):59–69. https://doi.org/10.1111/nyas.13466

    Article  CAS  PubMed  Google Scholar 

  106. Fu L, Han B, Zhou Y, Ren J, Cao W, Patel G, Kai G, Zhang J (2020) The anticancer properties of tanshinones and the pharmacological effects of their active ingredients. Front Pharmacol 11:193. https://doi.org/10.3389/fphar.2020.00193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Greenshields AL, Fernando W, Hoskin DW (2019) The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp Mol Pathol 107:10–22. https://doi.org/10.1016/j.yexmp.2019.01.006

    Article  CAS  PubMed  Google Scholar 

  108. Armando RG, Mengual Gomez DL, Gomez DE (2020) New drugs are not enough-drug repositioning in oncology: an update. Int J Oncol 56(3):651–684. https://doi.org/10.3892/ijo.2020.4966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ferreira PMP, Ferreira JRDO, Sousa RWRD, Bezerra DP, Militão GCG (2021) Aminoquinolines as translational models for drug repurposing: anticancer adjuvant properties and toxicokinetic-related features. J Oncol 2021(1):3569349. https://doi.org/10.1155/2021/3569349

    Article  PubMed  PubMed Central  Google Scholar 

  110. Kasi PD, Tamilselvam R, Skalicka-Woźniak K, Nabavi SF, Daglia M, Bishayee A, Pazoki-Toroudi H, Nabavi SM (2016) Molecular targets of curcumin for cancer therapy: an updated review. Tumor Biol 37:13017–13028. https://doi.org/10.1007/s13277-016-5183-y

    Article  CAS  Google Scholar 

  111. Yu M, Li R, Zhang J (2016) Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer. Biochem Biophys Res Commun 471(4):639–645. https://doi.org/10.1016/j.bbrc.2016.02.072

    Article  CAS  PubMed  Google Scholar 

  112. Javed Z, Khan K, Herrera-Bravo J, Naeem S, Iqbal MJ, Sadia H, Sharifi-Rad J (2021) Genistein as a regulator of signaling pathways and microRNAs in different types of cancers. Cancer Cell Int 21:1–12. https://doi.org/10.1186/s12935-021-02091-8

    Article  CAS  Google Scholar 

  113. Zhang Y, Guo S, Fang J, Peng B, Zhang Y, Cao T (2018) Tanshinone IIA inhibits cell proliferation and tumor growth by downregulating STAT3 in human gastric cancer. Exp Ther Med 16(4):2931–2937. https://doi.org/10.3892/etm.2018.6562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Xiao Y, Tian C, Huang T, Han B, Wang M, Ma H, Li Z, Ye X, Li X (2018) 8-Cetylberberine inhibits growth of lung cancer in vitro and in vivo. Life Sci 192:259–269. https://doi.org/10.1016/j.lfs.2017.11.012

    Article  CAS  PubMed  Google Scholar 

  115. Menegazzi M, Masiello P, Novelli M (2021) Anti-tumor activity of Hypericum perforatum L. and hyperforin through modulation of inflammatory signaling, ROS generation and proton dynamics. Antioxidants 10(1):18. https://doi.org/10.3390/antiox10010018

    Article  CAS  Google Scholar 

  116. Faria J, Negalha G, Azevedo A, Martel F (2019) Metformin and breast cancer: molecular targets. J Mammary Gland Biol Neoplasia 24(2):111–123. https://doi.org/10.1007/s10911-019-09429-z

    Article  CAS  PubMed  Google Scholar 

  117. Singh S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1667. https://doi.org/10.3389/fpls.2016.01667

    Article  PubMed  PubMed Central  Google Scholar 

  118. Mohi-Ud-Din R, Chawla A, Sharma P, Mir PA, Potoo FH, Reiner Z, Calina D (2023) Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects. Eur J Med Res 28(1):345. https://doi.org/10.1186/s40001-023-01275-4

    Article  PubMed  PubMed Central  Google Scholar 

  119. Ivanescu B, Miron A, Corciova A (2015) Sesquiterpene lactones from Artemisia genus: biological activities and methods of analysis. J Anal Methods Chem 2015(1):247685. https://doi.org/10.1155/2015/247685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chen GQ, Benthani FA, Wu J, Liang D, Bian ZX, Jiang X (2020) Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ 27(1):242–254. https://doi.org/10.1038/s41418-019-0352-3

    Article  CAS  PubMed  Google Scholar 

  121. Bhaw-Luximon A, Jhurry D (2017) Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives. Cancer Chemother Pharmacol 79:451–466. https://doi.org/10.1007/s00280-017-3251-7

    Article  CAS  PubMed  Google Scholar 

  122. Li Z, Li Q, Wu J, Wang M, Yu J (2016) Artemisinin and its derivatives as a repurposing anticancer agent: What else do we need to do? Molecules 21(10):1331. https://doi.org/10.3390/molecules21101331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 5(1):209. https://doi.org/10.1038/s41392-020-00312-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kolawole OR, Kashfi K (2022) NSAIDs and cancer resolution: new paradigms beyond cyclooxygenase. Int J Mol Sci 23(3):1432. https://doi.org/10.3390/ijms23031432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang Y, Liu Y, Du X, Ma H, Yao J (2020) The anti-cancer mechanisms of berberine: a review. Cancer Manag Res 30:695–702. https://doi.org/10.2147/CMAR.S242329

    Article  Google Scholar 

  126. Cechakova L, Ondrej M, Pavlik V, Jost P, Cizkova D, Bezrouk A, Tichy A (2019) A potent autophagy inhibitor (Lys05) enhances the impact of ionizing radiation on human lung cancer cells H1299. Int J Mol Sci 20(23):5881. https://doi.org/10.3390/ijms20235881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shi TT, Yu XX, Yan LJ, Xiao HT (2017) Research progress of hydroxychloroquine and autophagy inhibitors on cancer. Cancer Chemother Pharmacol 79:287–294. https://doi.org/10.1007/s00280-016-3197-1

    Article  CAS  PubMed  Google Scholar 

  128. Farghadani R, Naidu R (2021) Curcumin: modulator of key molecular signaling pathways in hormone-independent breast cancer. Cancers 13(14):3427. https://doi.org/10.3390/cancers13143427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li M, Li B, Xia ZM, Tian Y, Zhang D, Rui WJ, Dong JX, Xiao FJ (2019) Anticancer effects of five biflavonoids from Ginkgo biloba L. male flowers in vitro. Molecules 24(8):1496. https://doi.org/10.3390/molecules24081496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Novelli M, Masiello P, Beffy P, Menegazzi M (2020) Protective role of St. John’s wort and its components hyperforin and hypericin against diabetes through inhibition of inflammatory signaling: evidence from in vitro and in vivo studies. Int J Mol Sci 21(21):8108. https://doi.org/10.3390/ijms21218108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Irie H, Banno K, Yanokura M, Iida M, Adachi M, Nakamura K, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E (2016) Metformin: a candidate for the treatment of gynecological tumors based on drug repositioning. Oncol Lett 11(2):1287–1293. https://doi.org/10.3892/ol.2016.4075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS (2017) The role of resveratrol in cancer therapy. Int J Mol Sci 18(12):2589. https://doi.org/10.3390/ijms18122589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Nurgali K, Jagoe RT, Abalo R (2018) Adverse effects of cancer chemotherapy: anything new to improve tolerance and reduce sequelae? Front Pharmacol 9:245. https://doi.org/10.3389/fphar.2018.00245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zyad A, Leouifoudi I, Tilaoui M, Mouse HA, Khouchani M, Jaafari A (2018) Natural products as cytotoxic agents in chemotherapy against cancer. Cytotoxicity 5:65–88. https://doi.org/10.5772/intechopen.72744

    Article  CAS  Google Scholar 

  135. Wang B, Deng AJ, Li ZH, Wang N, Qin HL (2020) Syntheses and structure–activity relationships in growth inhibition activity against human cancer cell lines of 12 substituted berberine derivatives. Molecules 25(8):1871. https://doi.org/10.3390/molecules25081871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ren Y, Wu S, Burdette JE, Cheng X, Kinghorn AD (2021) Structural insights into the interactions of digoxin and Na+/K+-ATPase and other targets for the inhibition of cancer cell proliferation. Molecules 26(12):3672. https://doi.org/10.3390/molecules26123672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Dong X, Zeng Y, Zhang Z, Fu J, You L, He Y, Hao Y, Gu Z, Yu Z, Qu C, Yin X (2021) Hypericin-mediated photodynamic therapy for the treatment of cancer: a review. J Pharm Pharmacol 73(4):425–436. https://doi.org/10.1093/jpp/rgaa018

    Article  PubMed  Google Scholar 

  138. Safe S, Nair V, Karki K (2018) Metformin-induced anticancer activities: recent insights. Biol Chem 399(4):321–335. https://doi.org/10.1515/hsz-2017-0271

    Article  CAS  PubMed  Google Scholar 

  139. Kundur S, Prayag A, Selvakumar P, Nguyen H, McKee L, Cruz C, Lakshmikuttyamma A (2019) Synergistic anticancer action of quercetin and curcumin against triple-negative breast cancer cell lines. J Cell Physiol 234(7):11103–11118. https://doi.org/10.1002/jcp.27761

    Article  CAS  PubMed  Google Scholar 

  140. Younes M, Mardirossian R, Rizk L, Fazlian T, Khairallah JP, Sleiman C, Rizk S (2022) The synergistic effects of curcumin and chemotherapeutic drugs in inhibiting metastatic, invasive and proliferative pathways. Plants 11(16):2137. https://doi.org/10.3390/plants11162137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bordoloi D, Kunnumakkara AB (2018) The potential of curcumin: a multitargeting agent in cancer cell chemosensitization. In: Role of nutraceuticals in cancer chemosensitization. Academic Press, pp 31–60. https://doi.org/10.2174/1574892810666151020101706

  142. Salla M, Pandya V, Bhullar KS, Kerek E, Wong YF, Losch R, Baksh S (2020) Resveratrol and resveratrol-aspirin hybrid compounds as potent intestinal anti-inflammatory and anti-tumor drugs. Molecules 25(17):3849. https://doi.org/10.3390/molecules25173849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Bishayee A (2023) Phenolic phytochemicals for prevention and treatment of colorectal cancer: a critical evaluation of in vivo studies. Cancers 15(3):993. https://doi.org/10.3390/cancers15030993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Khan S, Awan KA, Iqbal MJ (2022) Sulforaphane as a potential remedy against cancer: comprehensive mechanistic review. J Food Biochem 46(3):e13886. https://doi.org/10.1111/jfbc.13886

    Article  CAS  PubMed  Google Scholar 

  145. Rauf A, Imran M, Butt MS, Nadeem M, Peters DG, Mubarak MS (2018) Resveratrol as an anti-cancer agent: a review. Crit Rev Food Sci Nutr 58(9):1428–1447. https://doi.org/10.1080/10408398.2016.1263597

    Article  PubMed  Google Scholar 

  146. Pillai UJ, Ray A, Maan M, Dutta M (2023) Repurposing drugs targeting metabolic diseases for cancer therapeutics. Drug Discov Today. https://doi.org/10.1016/j.drudis.2023.103684

    Article  Google Scholar 

  147. Boshuizen J, Peeper DS (2020) Rational cancer treatment combinations: an urgent clinical need. Mol Cell 78(6):1002–1018. https://doi.org/10.1016/j.molcel.2020.05.031

    Article  CAS  PubMed  Google Scholar 

  148. Ioele G, Chieffallo M, Occhiuzzi MA, De Luca M, Garofalo A, Ragno G, Grande F (2022) Anticancer drugs: recent strategies to improve stability profile, pharmacokinetic and pharmacodynamic properties. Molecules 27(17):5436. https://doi.org/10.3390/molecules27175436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT (2021) Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20(3):200–216. https://doi.org/10.1038/s41573-020-00114-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the management of VFSTR (Deemed to be University) for providing a platform to carryout research work.

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Authors and Affiliations

  1. Department of Biotechnology, Vignan’s Foundation for Science Technology and Research, Vadlamudi, Guntur, Andhra Pradesh, 522213, India

    Indira Mikkili & Jagadish Kumar Suluvoy

  2. Department of Biotechnology, Karunya Institute of Technology and Sciences, Coimbatore, Tamil Nadu, 641114, India

    Jesse Joel Thathapudi & Pinaki Dey

  3. Srimaharshi Research Institute of Vedic Technology, Guntur, 522006, India

    Krupanidhi Srirama

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  1. Indira Mikkili
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  2. Jagadish Kumar Suluvoy
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  3. Jesse Joel Thathapudi
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  5. Krupanidhi Srirama
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Conceptualization: Indira Mikkili, Jagadisg Kumar Suluvoy; Writing and figures preparation: Indira Mikkili, Jagadisg Kumar Suluvoy; Review and editing: Jesse Joel T, Pinaki Dey, Krupanidhi Srirama. All authors read and approved for submission.

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Mikkili, I., Suluvoy, J.K., Thathapudi, J.J. et al. Synergistic strategies for cancer treatment: leveraging natural products, drug repurposing and molecular targets for integrated therapy. Beni-Suef Univ J Basic Appl Sci 13, 96 (2024). https://doi.org/10.1186/s43088-024-00556-z

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