Targeting apoptosis pathways in cancer by Chinese medicine. Li-Weber, M. Cancer Letters.

Targeting apoptosis pathways in cancer by Chinese medicine. Li-Weber, M. Cancer Letters. Article in Press, Corrected Proof, doi:10.1016/j.canlet.2010.07.015
Inspecting the history of drug development during the past half century demonstrates that natural resources represent a significant segment on the pharmaceutical market compared to randomly synthesized compounds. As compiled by the World Health Organization, more than 21,000 plant species have been used worldwide in herbal medicines. Herbs are an important source for drug development. The traditional Chinese medicine (TCM) has held and still holds an important position in primary health care in China and has been recently recognized by Western countries as a fertile source for revealing novel lead molecules for modern drug discovery. Although TCM has been used for thousands of years in China and has made great contributions to human health, its healing mechanisms at the molecular level are still largely unknown. So far, most TCM preparations are a combination of many natural products. The active compounds they contain can vary drastically depending on where they were grown or collected, or even from 1 year to the next in the same area. Therefore, it is necessary to identify the principle constituents and to understand the molecular mechanisms behind the efficacy observed.

The traditional Chinese medicine (TCM) uses a combination of different natural products based on practical experiences. To better understand the therapeutic functions of TCM, large efforts have been made to identify the principle constituents of TCM and to unravel the molecular mechanisms behind the efficacy observed. This review aims to summarize research results obtained from the most intensively studied TCM phytochemical compounds namely the alkaloids Berberine, Evodiamine; anthraquinones Emodin, Aloe-emodin, Rhein; the terpenoids Artemisinin, Celastrol, Triptolide; the flavones Apigenin, Chrysin, Wogonin, Baicalein; and the cyclopenta[b]benzofuran derivatives Rocaglamide. Most of them have been originally identified as anti-inflammatory and anti-viral reagents and are now known to also possess anti-tumor activities by targeting the apoptosis pathways in cancer.

Tumors show an increased metabolism and often a metabolic switch to aerobic glycolysis (Warburg effect) known to influence the redox status. Thus, tumors, particularly in advanced stage, produce elevated levels of ROS and show an altered redox status [1], [2] and [3]. Recent studies suggest that this biochemical property of cancer cells can be exploited to achieve therapeutic activity and selectivity because cancer cells with increased oxidative stress are likely more vulnerable by further ROS insults induced by exogenous agents [1] and [3]. Although a quite numbers of TCM compounds have been reported to kill tumor cells by generation of ROS, their mechanisms regarding to how ROS is induced are still largely unknown. Listed below are a few TCM compounds whose mechanisms of ROS generation have been investigated.

Reactive oxygen species and tumor biology are intertwined in a complex web, making it difficult to understand which came first, whether oxidants are required for tumor cell growth, and whether oxidant stress can be exploited therapeutically. Evidence suggests that transformed cells use ROS signals to drive proliferation and other events required for tumor progression. This confers a state of increased basal oxidative stress, making them vulnerable to chemotherapeutic agents that further augment ROS generation or that weaken antioxidant defenses of the cell. In this respect, it appears that tumor cells may die by the same systems they require.[3]
TCM compounds may target cancers by direct induction of ROS generation (e.g. Artemisinin, Artesunate and Emodin) or indirectly through depletion of GSH (e.g. Chrysin and Apigenin) or by increasing activities of enzymes (e.g. Xanthine oxidase) involved in the redox system (e.g. Berberine), by inducing DNA double-strand breaks (e.g. Berberine), by triggering Ca2+ release from ER (e.g. Wogonin), by inhibition of NF-κB activity (e.g. Triptolide, Celastrol and Wogonin), or by inhibition of transcription (e.g. Triptolide). The generation of ROS may contribute to mitochondrial damage, reduction of the mitochondrial transmembrane potential, release of cytochrome c and Smac, and subsequent caspase activation and apoptosis.
References

[1] D. Trachootham, J. Alexandre and P. Huang, Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?, Nat. Rev. Drug Disc. 8 (2009), pp. 579–591. View Record in Scopus | Cited By in Scopus (61)
[2] P.T. Szatrowski and C.F. Nathan, Production of large amounts of hydrogen peroxide by human tumor cells, Cancer Res. 51 (1991), pp. 794–798.
[3] P.T. Schumacker, Reactive oxygen species in cancer cells: live by the sword, die by the sword, Cancer Cell 10 (2006), pp. 175–176. Article |  PDF (189 K)  | View Record in Scopus | Cited By in Scopus (92)

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