Resveratrol induces apoptosis of diverse leukemia and epithelial cancer cell lines. Leukemia cells subject to resveratrol-induced apoptosis include early myeloid (K562, KCL22, HL60), monocytic (U937, THP1), B-lymphoid (WSU-CLL), and T-lymphoid (Jurkat).141920 Human carcinoma cell lines that apoptose in response to resveratrol span human breast cancer (MCF-7), prostate cancer (LNCaP, DU145), colorectal cancer (SW480), pancreatic cancer (PANC-1, AsPC-1), and esophageal cancer (Bic-1, Seg-1, HCE7).1421-25
Resveratrol induces apoptosis of MCF-7 cells by a p53-dependent mechanism. Induction of MCF-7 cell apoptosis by resveratrol was accompanied by induction of p53 phosphorylation and acetylation, post-translational modifications implicated in stabilization of p53 and consequent increased p53 abundance. Pifithrin-a, a selective p53 inhibitor, blocked resveratrol-induced p53 post-trans-lational modification and apoptosis of the MCF-7 cells.24 MCF-7 cells express wild-type p53.26 Resveratrol also induces p53-dependent apoptosis of DU145 cells, which harbor a mutated form of p53. Resveratrol-induced DU145 cell apoptosis was blocked by pifithrin-a, as were resveratrol-induced p53 phospho-rylation at serine-15, p53 accumulation, and p53 transcriptional activity in the prostate cancer cells.22 Activation of the Jun-NH2 kinase (JNK) pathway, which is triggered by various forms of stress, has been shown to stabilize p53, enhance p53 transcriptional activity, and potentiate p53-dependent apoptosis.27 Resveratrol potently induced JNK activation in mouse epidermal JB6 cells, and resveratrol-induced p53-dependent apoptosis was attenuated in JB6 cells transfected with dominant-negative JNK1 and in JNK1-/- and JNK2-/- mouse embryo fibro-blasts.28
An analysis of resveratrol-induced apoptosis of seven human leukemia cell lines (K562, KCL22, HL60, U937, THP1, WSU-CLL, and Jurkat) determined that Fas/Fas-ligand (FasL) did not contribute to the apoptotic responses of the cells, and that resveratrol induced caspase activity in each case. Interestingly, Z-VAD-FMK, a nondiscriminating inhibitor of caspases, did not increase the survival of resveratrol-treated K562 cells unless administered with the promiscuous protease-inhibitor leupeptin, which was also ineffective alone.20 A study focused on resveratrol-induced apoptosis of U937 cells found that apoptosis was associated with caspase-3 activation and was blocked by Z-VAD-FMK as well as by enforced Bcl-2 expression. Resveratrol-induced apoptosis was associated with loss of the IAPs cIAP1 and cIAP2, but XIAP and survivin levels were unchanged.19 A safety concern noted in Ferry-Dumazet et al.20 is that, although resveratrol did not affect resting normal human peripheral blood lymphocytes (PBL), PHA-activated normal PBL were more sensitive to resveratrol-induced growth suppression/apoptosis than several leukemia cell lines.
A detailed analysis of resveratrol-induced apoptosis in human colon cancer SW480 cells revealed that resveratrol activates the death-receptor apoptosis pathway Fas/FasL by recruiting the death-receptor Fas to cluster and enter the death-
inducing signaling complex (DISC) with the adaptor molecule FADD (Fas-associating protein with death domain) and caspase-8; interestingly, resveratrol-induced SW480 apoptosis was unaffected by an antagonistic Fas Ab and by ligand sequestration by FasL Ab, but was abrogated by dominant-negative FADD.23 While the focus of this chapter is cancer prevention, there is growing interest in the use of resveratrol and other cancer-preventive phytochemicals in cancer therapy. Remarkably, the action of resveratrol in SW480 cells bears some resemblance to apoptosis induction by the highly effective cancer therapeutic taxol, which triggers leukemia cell apoptosis primarily through caspase-10 activation by a death receptor-independent, FADD-dependent mechanism.29
18.6 NF-kB SURVIVAL PATHWAY SUPPRESSION BY RESVERATROL
The transcription-factor NF-kB (nuclear factor-KB) induces the expression of key survival genes, e.g., Bcl-XL, XIAP, and cFLIP, pro-inflammatory cytokines, e.g., interleukin-1 (IL-1) and tumor necrosis factor (TNF), and other genes involved in cell proliferation, e.g., cyclin D1.30 Based on its pro-inflammatory, anti-apop-totic, and oncogenic activity, NF-kB is viewed as an important target in cancer prevention and therapy.30 NF-kB is sequestered in the cytoplasm in an inactive state as a complex with the inhibitory protein IKBa. NF-kB activation entails IKBa phosphorylation by the kinase complex IKK. This triggers ubiquitination and proteasomal degradation of IKBa, thus liberating NF-kB to translocate to the nucleus and activate expression of target genes. A study in human monocyte THP-1 cells revealed that resveratrol potently suppresses NF-KB-dependent gene expression, whether induced by TNF or LPS (lipopolysaccharide) by targeting the NF-kB pathway at a point upstream of IKK. This was demonstrated by showing that resveratrol inhibition of TNF-induced NF-kB activation was associated with suppression of IKK activation, IKBa phosphorylation, and IKBa degradation. IKK was ruled out as the direct target by showing that resveratrol had no effect on the activity of the isolated kinase complex, with the implication that the resveratrol target was upstream of IKK in the NF-kB pathway.31
A number of NF-KB-inducible genes correspond to gene products that induce NF-kB activation, forming a positive feedback loop, e.g., TNF and IL-1p. IL-1P is a critical cytokine in the proliferation of acute myeloid leukemia (AML) cells. Estrov et al.32 have established that resveratrol suppresses IL-1P-induced NF-kB activation in the AML cell line OCIM2 and concomitantly attenuates production of the IL-1P protein by the cells. The significance of these findings to cancer prevention is strongly suggested by the analysis of clinical AML specimens in the report. Resveratrol inhibited the colony-forming growth of freshly isolated AML blast colony-forming cells in a concentration-dependent manner, and colony formation was partially rescued by exogenous IL-1p.32
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