Initiation of apoptosis and suppression of angiogenesis
Professor and Glaxo Chair in Pharmaceutics, Center for Cancer Chemoprevention, Department of Pharmaceutics, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ, United States
AIM: To successfully control cancer, a global multi-prone approach to mitigate the multistage of carcinogenesis, which includes initiation, promotion and progression, is clearly desirable. Cancer chemoprevention is fast emerging as a discipline with very promising potential, which has its rationale in controlling the multistage process of carcinogenesis, in the early, premalignant stages, before the appearance of any clinical symptoms. A growing number of natural and synthetic chemicals with cancer chemopreventive property exert multiple signaling mechanisms and consequently diverse pharmacological effects. These effects include blocking initiation, promotion and progression via initiation of apoptosis, differentiation and/or suppression of angiogenesis and proliferation. These chemopreventive compounds include dietary flavonoids (epigallocatechin gallate (EGCG), genistein), non-steroidal anti-inflammatory drugs (NSAIDs), retinoids, and others. METHODS: This lecture will review and cover the latest strategies and knowledge in cancer chemoprevention as relate to signaling events leading to initiation of apoptosis and suppression of angiogenesis. RESULTS: Many dietary chemopreventive compounds including green tea polyphenols EGCG, as well as others, can differentially modulate signaling mitogen-activated protein kinases (MAPK; ERK, JNK and p38), stimulate loss of mitochondrial membrance potential,cytochrome c release, and activation of caspase-3, -8 and â9 preceding apoptosis, modulation of transcription factors Nrf2/ARE, AP-1, NF-kappa-B, leading to changes in gene expression of targets genes including glutathione S-transferases (GSTs), cyclooxygenases (COX-2), or vascular endothelial growth factor (VEGF), with the biological consequences of initiation of apoptosis, suppression of angiogenesis and others. In addition, antioxidant N-acetyl cysteine (NAC) and tea catechin EGCG have been shown to inhibit matrix metalloproteinases (MMPs) activities, which further contribute to anti-angiogenic effects. CONCLUSIONS: Many currently developed cancer chemopreventive agents display multiple signaling mechanisms and multiple anti-cancer effects. The presently clinically used chemopreventive drugs, including NSAIDs, tamoxifen or retinoids, can also induce apoptosis and suppress angiogenesis. In summary, the use of non-toxic cancer chemopreventive compounds is fast emerging as a promising potential to control the multistage of cancer initiation, promotion and progression, which ultimately would lead to improve strategy to control of cancer.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 1001 (Intervention strategies).