Highlights• Cancer is second deadly disease after cardiovascular diseases.• There is a tremendous need to discover novel safer and more effective anticancer agents.• Plants serve as a basis for promising therapeutic agents for cancer treatment.• Important plant derived anticancer agents have been discussed here.• Some potential plant derived lead molecules have also been discussed. *Corresponding author:Centre for Microbial Ecology and Genomics, Graphical abstract

This review attempts to portray the discovery and development of anticancer agents/drugs from diverse natural sources. Natural molecules from these natural sources including plants, microbes and marine organisms have been the basis of treatment of human diseases since the ancient times. Compounds derived from nature have been important sources of new drugs and also serve as templates for synthetic modification. Many successful anti-cancer drugs currently in use are naturally derived or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents.

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Abstract:This review surveys the diversity of natural products derived from terrestrial plants, microorganisms, marine organisms and fungi and utilised in the treatment of various diseases.A wide spectrum of compounds derived from these sources has found many applications in the fields of medicine, pharmacy and general biology. The enormous structural diversity of natural products and their medicinal significance has led researchers to predict that screening natural resources will generate new -lead‖ compounds. It is well established that structural analogues with greater pharmacological activity and fewer side effects can be generated by molecular modification of the functional groups of such lead compounds.

Withania somnifera (L) Dunal, commonly known as ashwagandha or Indian ginseng, is the source of large number of pharmacologically active withanolides. Withaferin-A (WS-3), a major withanolide of W. somnifera, has been proven to be an effective anti-cancer molecule. In this study, a liquid culture system for shoot proliferation, biomass accumulation and withaferin-A production of an elite accession (AGB002) of W. somnifera was investigated. The nodal explants cultured on Murashige and Skoog (MS) semi-solid medium supplemented with various concentrations of 6-benzyl adenine (BA) and Kinetin (Kn) 2 elicited varied responses. The highest number of regenerated shoots per ex-plant (35±3.25) and the maximum average shoot length (5.0± 0.25 cm) were recorded on MS medium supplemented with BA (5.0 μM). The shoots were further proliferated in half and full strength MS liquid medium supplemented with the same concentration BA. It was interesting to note that shoots cultured on MS half strength liquid medium fortified with 4 gL-1 FW (fresh weight) shoot inoculum mass derived from 5 week old nodal explants of W. somnifera showed highest accumulation of biomass and withaferin A content in 5 weeks.Withaferin A was produced in relatively high amounts The production of Withania drugs in India has been esti-mated about 9,127-tonnes per year far exceeding the annual plant production of 5,905-tonnes (Sivanandhan et al. 2012). Presently, whole plants are being harvested from wild for the production of Withania-based medicines to meet a growing demand of pharmaceutical industries. This random harvesting of ashwagandha germplasm for withanolide production is economically and environmentally unwise as it causes loss of genetic diversity and habitat destruction. An elegant alter-native to these apparent hurdles would be to identify the genotype rich in bioactive withanolides, develop high yielding in vitro production methods and to and improve them genetically for cultivation to meet the demand of bioactive withanolides.Plant cell and organ cultures offer an excellent opportunity for homogenous, controlled production of metabolites, throughout the year, especially when we take commercial demand into account. They not only facilitate the de novo synthesis of novel compounds, but also are able to produce metabolites, even in higher amounts than in the intact plants. Over recent decades, several attempts have been made to improve withanolide production by tissue culture (Ray and Jha 2001;Sharada et al. 2007;Dewir et al. 2010). Production of bioactive molecules by in-vitro liquid culturing techniques has gained considerable attention in recent years, and such methods are increasingly attractive alternatives to whole plant cultivation for production of high value phytochemicals (Pati et al. 2010;Gawde and Paratkar 2012). 4The pure compound of WS-3 is commercially obtained from the aerial parts of W. somnifera plants but the production is not sufficient for the current market demand. The chemical synthesis of withaferin A is comp...

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Withania somnifera (L.) Dunal (Indian ginseng) is a high value medicinal plant. It synthesizes a large array of biologically active withanolides. In this study, two month old seedlings of AGB002 (wild genotype) and AGB025 (cultivated genotype) of W. somnifera were subjected to cold stress (4 • C) under controlled envi-ronment. Plants were analyzed for three medicinally important secondary metabolites (withanolide A, withanone and withaferin A), lipid peroxidation (MDA), cell injury, superoxide radical (O 2 •− ) accumula-tion and anti-oxidative enzymes activities such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR). Increases in the titers of superoxide anion and MDA were observed from day 1 to day 7 in both genotypes, although the increase on the first day of exposure was significantly higher. Enzymatic activities of SOD, CAT, APX and GR also showed an increasing trend in both genotypes and reached a maximum on day 7 of the cold temperature exposure; however, this increase was higher in AGB002 than AGB025. Withanolide A (WS-1) in the roots of both genotypes sig-nificantly decreased on the first day of cold exposure and then showed a recovery until day 7. WS-1 was not detected in the leaves of either genotype. Withanone (WS-2) content in the leaves also decreased towards the end of the cold period in both genotypes. Cold stress also elicited the accumulation of WS-2 in AGB025, but was not detectable in control seedlings. At maturity, WS-2 was also detected in control plants. Furthermore, a significant increase in the leaf withaferin A (WS-3) content was recorded from day 1 to day 7 of the cold exposure in both the genotypes, suggesting the possible involvement of with-anolides in cold-protection. AGB002 showed comparatively higher accumulation of antioxidant enzymes and selected marker withanolides than AGB025, indicating that AGB002 is better adapted to cold than AGB025. It could be inferred from these observations that cold stress induces bioactive withanolide accu-mulation in W. somnifera as a mechanism for scavenging reactive oxygen species (ROS). These studies also provide an impetus for enhancing the withanolide accumulation in W. somnifera using controlled environment technology.

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