ReviewNatural products: An upcoming therapeutic approach to cancer
Introduction
Cancer is considered as a major cause of death worldwide (Antoni et al., 2017). Cancer is a group of diseases where uncontrolled cell growth occurs and has the potential to spread to other parts of the body. The tumor suppressing mechanisms present in a normal cell always distinguishes between abnormally growing cancer cells and normal cells but the problem arises when the functions of these tumor suppressing genes get restricted by different environmental factors (like pollution, radiation, certain infections, etc.) or human habits (like tobacco, poor diet, alcohol, etc.) (Aruoma et al., 2014; Bagnardi et al., 2014; Gallagher et al., 2017; Leon et al., 2015; Massarweh and El-Serag, 2017; Raaschou-Nielsen et al., 2016; Taylor et al., 2017). In 2018, about 18.1 million (17.0 million excluding nonmelanoma skin cancer) new cases of cancer and 9.6 million deaths from cancer (9.5 million excluding nonmelanoma skin cancers) were reported. Cancer has become a major cause of mortality all over the world irrespective of human development. Lung cancer is the most identified cancer (11.6% of the total cases), narrowly followed by female breast cancer (11.6%), prostate cancer (7.1%) and colorectal cancer (6.1%). Moreover, lung cancer is also the major reason of cancer death (18.4% of the total cancer deaths), followed by colorectal cancer (9.2%), stomach cancer (8.2%) and liver cancer (8.2%) (Bray et al., 2018).
Natural products isolated from medicinal plants have been used for the treatment of various diseases from ancient times. The first use of natural products as medicine was dated back in 2600 BC in Mesopotamia. The “Ebers Papyrus” records of more than 700 drugs back in 1550 BC are also well preserved (Borchardt, 2002; Cragg and Newman, 2013b). Similarly, traditional Chinese medicine (TCM) is well documented over thousands of years (Unschuld, 1985; Yang et al., 2017c) and the Indian Ayurveda system is practiced since the 1st millennium BC (Parasuraman et al., 2014; Patwardhan and Gautam, 2005). Natural product-based drug discovery is related to some challenges, like availability, identification of bioactive compounds, difficulty in the collection of wild specimen and incompatibility of natural products with high throughput screening (HTS) (Atanasov et al., 2015). Further evaluation of the exact molecular mechanism of action of natural products is a difficult task. Due to these difficulties, pharmaceutical industries shifted their main focus towards synthetic compounds for new drug discoveries. But the results obtained from the newly introduced synthetic drugs in the 1990s did not match the expectations (Scannell et al., 2012). The approval rates of these drugs by the US Food and Drug Administration (FDA) was low. Due to these reasons, the interest in natural product-based drug discovery was revived.
Different natural phytochemicals used for the treatment of various diseases including cancer are becoming important for drug discovery and research (Dutta et al., 2018; Jagtap et al., 2009; Jeong et al., 2006; Manna et al., 2006; Pal et al., 2012, 2015; Sadhukhan et al., 2018a, 2018b; Saha et al., 2018). These phytochemicals are found to be effective against various types of cancer. They show such effectiveness by alternating the cancer initiation, development and progression as well as interrupting several mechanisms like differentiation, cellular proliferation, angiogenesis, apoptosis and metastasis (Amin et al., 2009; Huang et al., 2009; Nobili et al., 2009). Irrespective of cancer specificity, recent research indicates that most of the cancer onsets are caused by mutations in protein coding-genes and alteration in protein production (Davies et al., 2002; Nik-Zainal et al., 2016). Several cell signaling proteins such as growth factors and their receptors, anti-apoptotic proteins, tumor suppressors and transcription factors are altered in cancer and can be treated as therapeutic targets (Gotwals et al., 2017; Topalian et al., 2015). Programmed cell death, especially apoptosis and autophagy, are the natural obstacles that limit cancer cells progression and development. These mechanisms may jointly decide the fate of cancer cells. They play an important role during tissue homeostasis preservation and elimination of cancerous cells (Esteve and Knecht, 2011). However, cancer cells develop different approaches to avoid cell death by producing epigenetic modifications or genetic mutations in the major component of programmed cell death pathways (Coyle et al., 2017). These cells become resistant to programmed cell death and become tumor-relapsing self-renewal cancer stems cells (CSCs). CSCs display many features of embryonic or tissue stem cells (Zhang et al., 2019). They exhibit determined activation of one or more highly conserved tissue developmental pathway, including the Notch, Hedgehog (HH), and Wnt pathways (Takebe et al., 2015a). These pathways are the key modulator of tumorigenicity of cancer stem cells. Increasing evidence indicates that these embryonic pathways can crosstalk with other cellular signaling pathways (Apoptosis, autophagy, NFκB, MAPK, PI3K, and EGF) (Sever and Brugge, 2015). Recent studies indicate that in anticancer therapy, we can use different natural compounds targeting programmed cell death mechanism or embryonic developmental pathways to restored normal tissue homeostasis (Ke et al., 2016; Oren and Smith, 2017; Varoni et al., 2016). Although diverse approaches are accessible for the discovery of novel and potential therapeutic agents modulating cell signaling cascades, natural products from medicinal plants and other sources seems to be the most cost-effective and promising approach (Atanasov et al., 2015; Dutta et al., 2017, 2018).
Therefore, identification of natural compounds which selectively inhibit the initiation, progression, metastasis of carcinogenesis and elimination of the CSCs at the same time, without cytotoxic effects in normal cells, has become important.
Section snippets
Cell signaling pathways as therapeutic targets for cancer therapy
Cellular signaling pathways are complex communication network made up of small three-dimensional signaling cascades comprising of many signaling proteins. The actions of these proteins are specific to cell type, cell site and intra-molecular interactions. Alteration in these proteins homeostasis leads to the diverse diseased conditions. In case of cancer, alternation of cell signaling cascades may lead to an elevated immune response, increased cancer cell proliferation and survival (Hanahan and
Conclusion
This review article provides a deep insight about the role of natural products in cancer therapy by modulating programmed cell death and self-renewal developmental pathway. Natural compounds are emerging as a potential therapeutic agent in the field of anticancer research due to their easy availability and cost-effectiveness. Numerous natural compounds are in preclinical or clinical trials for cancer treatment (Cragg and Newman, 2013a; Dutta et al., 2017). Different epidemiological studies
Conflict of interest statement
The authors declared no conflict of interest.
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