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Lignans: a versatile source of anticancer drugs

Abstract

Background

Cancer is considered as the second deadliest disease globally. Plants have continuously offered unique secondary metabolites with remarkable biological applications. Lignans have gained great importance due to their biological activity. Previous studies revealed that the most remarkable bioactivity of lignan class of molecules is anticancer. They are derived from the oxidative dimerization of two phenylpropanoid units. This review covers the isolated anticancer lignans and their mechanistic aspects.

Main body

A bibliographic investigation was performed by analyzing the information available on anticancer lignans in the internationally accepted scientific databases including Web of Science, SciFinder, PubMed, Scopus, and Google Scholar. In this review we have tried to sum up the isolated anticancerous lignan, its source, active plant part, extract and various cell lines used to establish different studies. Here we have included a total number of 113 natural lignans. Many studies that mainly performed in human cell lines have reported. Very few plants have been evaluated for their in vivo anticancer activity.

Conclusion

It can be concluded that in near future the lignans may be an effective pharmacon for the treatment of cancer. Fruitful areas of future research may be in modifying natural lignans or synthesizing new lignans with structural diversity and potent pharmacological activities. Extensive studies are needed to be done highlighting the mechanism of anticancer action of explored and unexplored plants. The data will definitely attract many researchers to start further experimentation that might lead to the drugs for the cancer treatment.

Graphical Abstract

Background

There is a great burden of disease internationally and cancer is in the top priority due to its high incidence rate that causes disability and premature mortality among human populations [1].

Cancer is not a single disease but it is a group of 100 different and distinguishing disorders that affect the entire physiological balances [2]. It is an uncontrolled growth of cells that have damaged DNA expression [3]. If the spread of these abnormal cells is not managed with certain means, it can lead to worse situations or may be death. These abnormal cells are termed as cancer cells, malignant cells, or tumor cells. Many cancers that comprises of abnormal cells are further recognized by the name of the organ that the abnormal cells originated from (for example, breast cancer, lung cancer, prostate cancer, and colorectal cancer). There are various kinds of cancers depends upon the type of genes associated with specific cancer like sarcomas, carcinomas, leukemia, and lymphomas. Carcinogenesis is a multi-leveled process consists of three noticeable stages, i.e., initiation, promotion, and progression [4]. It is the prime result of disturbances that occurred in two types of genes, tumor suppressor genes (TSG) and oncogenes.

Deaths from cancer are rising continuously worldwide with an estimated 11.5 million deaths in 2030 [5]. The International Agency for Research on Cancer (IARC) estimated a shocking number of 19.3 million new cases including every possible distribution criteria (Fig. 1a, b) and approx 10 million of reported death worldwide [6].

Fig. 1
figure 1

a Global cancer cases distribution types including all age groups of females. Source: GLOBOCAN, 2020. b Global cancer cases distribution types including all age groups of males. Source: GLOBOCAN, 2020

Globally, non-communicable diseases (NCDs) accounted for 71% of total deaths. In India, NCDs were estimated to account for 63% of all deaths, and cancer was one of the leading causes (9%). The projected number of patients with cancer in India is 1,392,179 for the year 2020, and the common five leading origins are breast, lung, mouth, cervix uteri, and tongue [7]. Persons with any type of existing cancer are prone to get affected with coronavirus (SARS-CoV-2), and it is a deadly combination for individuals [8]. Studies revealed that prostate and breast cancer constitutes major types of cancer found, respectively, in men and women [9]. In children the blood cancer and the cancers related to the brain and lymph nodes are more frequent than other types of cancer [10, 11]. There are certain risk factors that increase the development of cancer in any person such as ageing, tobacco, ionizing radiation, some chemical compounds, some viruses and bacteria, alcohol consumption, family history of cancer, certain hormones, and overweight [12].

The treatment options of cancer involve surgery of tumor, radiotherapy and chemotherapy depends upon the stage and location of tumor [13]. But these treatments are very costly and require highly specialized health professionals [14]. Additionally, these chemotherapeutic agents are not free from side effects like myelosuppression, mucositis, alopecia, cardiotoxicity, neurotoxicity, immunosuppression, etc. An ideal anticancer drug would specifically be cytotoxic toward the cancer cells only and research findings suggests that phytochemicals and their derivatives are emerging alternatives for better and less toxic chemotherapeutic agents [13].

Various active compounds such as podophyllotoxin, vincristine, vinblastine, taxol, etc., have been isolated from plants, and these molecules acted as lead metabolites to modify and yield analogues better than the parent compound for activity with low toxicity and improved bioavailability [15,16,17].

There are diverse classes of secondary metabolites which are biosynthesized by plants and, among them, lignans are identified as the major group of natural products with a broad range of important bioactivities.

Main text

Lignans are the class of plant secondary metabolites derived from the phenylpropanoid pathway and was first introduced by Haworth [18]. They play an important role in plant protection and are also proved to be fruitful in human nutrition and medicine [19]. The chief sources of dietary lignans are various vegetables and fruits, legumes, whole grain cereals, and oilseeds [20, 21]. Sesame and flax seeds are the edible plant components which are the most concentrated sources of lignans [22].

Chemistry of lignans

It is well-established that the supergroup of natural phenolics is biosynthesized through the shikimic acid pathway. The biodiversity of this lignan class of molecules is found in various parts of more than 60 families of plants and they are potential bioactive principles toward cancerous cells. Beside their cytotoxic property they are also useful to treat diabetes, oxidation of living cells as antioxidants, cardiovascular diseases, microbial infections, and other major or minor inflammatory responses [23, 24]. As per the earlier findings, the basic structure of lignan contains the nine carbon (in a C6-C3 fusion) phenylpropane unit (Fig. 2a) from cinnamyl structures [25] which was redefined by Haworth [18] as dimer of C6-C3 unit via β-β′ bonding (Fig. 2b). Besides this basic hydrocarbon skeleton they possess numerous additional side groups either in the form of aliphatic or aromatic origin and they are classified accordingly. There are eight subtypes of major lignans (Fig. 3) such as dibenzylbutane (e.g., Enterodiol), dibenzylbutyrolactone (e.g., Enterolactone), dibenzylbutyrolactol (e.g., Gnetucleistol F), dibenzocyclooctadiene (e.g., Gomisins), aryltetralin (e.g., Podophyllotoxins), arylnaphthalene (e.g., Justcidins), furan (e.g., Belischmins), and furofuran (e.g., Epimagnolin) derivatives. Except these eight subtypes, they are also diversified based on the presence or absence of oxygen [26, 27]. Hybrid lignans are molecules which have other secondary metabolites like flavonoids (flavolignans), coumarins (coumarinolignans), xanthones (xantholignans), stilbenes (stilbenolignans), etc., and possess lignan like biological and chemical properties.

Fig. 2
figure 2

a Phenylpropane unit. b Dimer of C6-C3 unit via β-β′ bonding

Fig. 3
figure 3

Eight chemical classes of lignan molecules

Fig. 4
figure 4figure 4figure 4

Chemical structures of anticancer isolated lignans from plants

The discovery of Podophyllotoxins as gold standard in leading lignans along with establishing its cytotoxic property and topoisomerase-II inhibitory potentials helped the research community to develop other clinically important drugs like etoposide, teniposide, clinical candidates like Etopophos, NK611, GL331, etc. [28]. Ward reported a total number of 83 synthetic and transformational schemes including stereospecific and asymmetric consideration [29] to obtain them in laboratory.

There is persistent interest in the cancer-protective effects of lignans, which have been shown to have an advantageous anti-tumor effect throughout the early phases of carcinogenesis. The present review, summarizes the recent literature which deals with the lignans isolated from plants having anticancer potential with their reported mechanism of action which are listed in Table 1. Lignans has been considered as the promising anticancer agents.

Table 1 List of lignans isolated from plant with anticancer activity

Material and methods

The bibliography was crucially analyzed from worldwide established scientific databases like SCOPUS, PubMed, ScienceDirect, Springerlink, Web of Science, Wiley, SciFinder, and Google Scholar. The botanical names of these selected plant species were verified from the plant list. The inclusion criteria for the selection of data are lignans isolated from Medicinal plants with reported anticancer activity. Both the reviews and the research articles on medicinal plants are considered. The search terms were lignans, anticancer plants containing lignans, chemistry of lignans without narrowing or limiting search items.

Conclusions

Lignans are secondary metabolites are also phenolic in nature and have diversity in biological activities. Previous studies revealed that the most remarkable bioactivity of lignan class of molecules are antioxidant and anticancer. This review covers a considerable number of naturally obtained lignans that are reported to have anticancer potential. In this review we have tried to sum up the isolated anti-cancerous lignan, its source, active plant part, extract and various cell lines used to establish different studies. Here we have included a total 113 numbers of natural lignans. Many studies that mainly performed in human cell lines have reported inhibition of enzymes that retards tumor growth. Very few plants have been evaluated for their in vivo anticancer activity.

It can be concluded that in near future the lignans may be an effective pharmacon for the treatment of cancer. Fruitful areas of future research may be in modifying natural lignans or synthesizing new lignans with structural diversity and potent pharmacological activities. However, among the vast numbers of existing plants on this planet, only a few species have been studied so far for their anticancer principles. Extensive studies are needed to be done highlighting the mechanism of anticancer action of explored and unexplored plants.

Potent anticancer lignans reported in this review needed to be further explored in clinical trials on different models for their effectiveness, toxicological studies, and also targeting particular genotoxic profile against a wide range of cancer in both in vitro and in vivo. These compounds are obtained from plants in very minute quantities so this is one of the main challenges to be addressed in the future and their total synthesis in order to allow further bioactivity studies. The data will definitely attract many researchers to start further experimentation that might lead to the drugs for the cancer treatment and to manufacture new herbal drugs which have significant anticancer potential.

Availability of data and materials

Not applicable.

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MM participated in conceptualization and writing of the manuscript. BCJ, PSB contributes in editing. AB, ANS review the final version of article. All authors read and approved the final manuscript.

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Mukhija, M., Joshi, B.C., Bairy, P.S. et al. Lignans: a versatile source of anticancer drugs. Beni-Suef Univ J Basic Appl Sci 11, 76 (2022). https://doi.org/10.1186/s43088-022-00256-6

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Keywords

  • Lignan
  • Anticancer plants
  • Podophyllotoxin
  • Cytotoxicity