ABSTRACT
In many studies, resveratrol has been shown to have a chemopreventive effect in various types of cancer cells. However, the biological activity of resveratrol is limited by its photosensitivity and metabolic instability. This study investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostate cancer cells. Hypoxic condition induced HIF-1α protein level in PC-3 cells in a time-dependent manner, and treatment with HS-1793 markedly decreased HIF-1α expression levels. HS-1793 also inhibited VEGF level. Mechanistically, HS-1793 inhibited HIF-1α and VEGF expression through multiple mechanisms. Firstly, HS-1793 inhibited phosphorylation of PI3K and Akt in PC-3 cells. Furthermore, HS-1793 substantially induced HIF-1α protein degradation through the proteasome pathway. Finally, HS-1793 inhibited hypoxia-induced PC-3 cell migration. These data suggest that HS-1793 may inhibit human prostate cancer progression and angiogenesis by inhibiting the expression of HIF-1α and VEGF. Moreover, HS-1793 showed more potent effects than resveratrol on the cytotoxic effects on PC-3 cells. Taken together, these results implied that HS-1793, a novel analogue of resveratrol, may be a new potent chemopreventive agent against human prostate cancer cells.
Subject(s)
Cell Hypoxia/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Naphthols/pharmacology , Prostatic Neoplasms/drug therapy , Resorcinols/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Cell Hypoxia/physiology , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Male , Neovascularization, Pathologic/prevention & control , Prostatic Neoplasms/pathology , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/biosynthesisABSTRACT
Resveratrol (3,4',5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. Several studies were undertaken to obtain synthetic analogues of resveratrol with potent anticancer activity. The aim of the present study was to investigate the effect of HS-1793 as a new resveratrol analog on apoptosis via the mitochondrial pathway in murine breast cancer cells. A pharmacological dose (1.3-20 µM) of HS-1793 exerted a cytotoxic effect on murine breast cancer cells resulting in apoptosis. HS-1793-mediated cytotoxicity in FM3A cells by several apoptotic events including mitochondrial cytochrome c release, activation of caspase-3 and PARP occurred. In addition, HS-1793 induced collapse of ∆Ψm and enhanced AIF and Endo G release from mitochondria while undergoing apoptosis. These results demonstrate that the cytotoxicity by HS-1793 in FM3A cells can mainly be attributed to apoptosis via a mitochondrial pathway by caspase activation or contributions of AIF and Endo G.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Naphthols/pharmacology , Resorcinols/pharmacology , Signal Transduction/drug effects , Animals , Caspase 3/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cytochromes c/metabolism , Female , G1 Phase/drug effects , Membrane Potential, Mitochondrial/drug effects , Mice , Poly(ADP-ribose) Polymerases/metabolismABSTRACT
Natural agents with the immunomodulating property have been gaining traction to be employed in the complementary therapy of cancer because the ineffectiveness of numerous therapeutic strategies may be related in part to the tumor-induced immunosuppressive phenotypes, especially regulatory T (Treg) cells found in the tumor microenvironment. The present study was undertaken to examine whether HS-1793, synthetic resvertrol analog free from the restriction of metabolic instability and high dose requirement of resveratrol, induces an in vivo anti-tumor effect in FM3A tumor bearing mice through the suppression of Treg cells, which contribute to an increase in tumor specific cytotoxic T cell responses. Intraperitoneal injections of HS-1793 showed not only therapeutic benefits on established tumors, but also preventive anti-tumor effects. Treg cells (CD4+CD25+Foxp3+ cells) were significantly reduced in the total splenocytes as well as tumor tissues from HS-1793-administered mice, and the production of TGF-ß inducing Treg showed a similar pattern. On the contrary, the administration of HS-1793 increased IFN-γ-expressing CD8+ T cells, upregulated IFN-γ production, and enhanced the cytotoxicity of splenocytes against FM3A tumor cells both in therapeutic and preventive experimental animals. These results demonstrated the suppressive role of HS-1793 on the function of Treg cells contributing to tumor specific cytotoxic T lymphocyte responses in tumor-bearing mice, which explained the underlying mechanism of the anti-tumor immunity of HS-1793.
