Mechanisms of resveratrol-induced apoptosis in cancer.

摘要

Despite major medical advances against cancer, systemic cytotoxicity and the resistance of many tumors to current treatment protocols still constitute major problems in cancer therapy. Resveratrol (RES) and beta-lapachone (beta-LAP) are two natural, non-toxic products with chemotherapeutic potential, capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms induced by these drugs are not well defined. Elucidation of the anticancer effects of RES and beta-LAP, and delineating the underlying mechanisms responsible for RES-induced apoptosis in cancer were the primary goals of this body of work. Using cancer cell lines of different origin, I demonstrate that RES and beta-LAP are anti-proliferative and induce apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of the mitochondrial membrane potential (DeltaPsim) by directly targeting mitochondria. This is followed by release of cytochrome c and Smac/DIABLO into the cytoplasm and the substantial increase in the activities of caspases-9 and -3. This work also demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca 2+]i), likely resulting from depletion of the endoplasmic reticulum (ER) stores of calcium. In caspase-3 deficient MCF-7 breast cancer cells apoptosis is mediated by the Ca2+-activated protease calpain, leading to the degradation of plasma membrane Ca 2+-ATPase isoform 1 (PMCA1) and further loss of Ca2+ homeostasis; the degradation is attenuated by buffering [Ca2+] i and blocked by calpain inhibitors. Mitochondrial permeability transition pore antagonists also blocked calpain activation.;In vivo studies demonstrate that RES treatment inhibits cancer growth with no systemic toxicity. Collectively, these results suggest a critical role for mitochondria and alterations in Ca2+ homeostasis during apoptosis initiated by RES, as well as the potential usefulness of RES as a non-toxic alternative for cancer treatment.