Jazirehi Ali R, Bonavida Benjamin
Department of Microbiology, Immunology and Molecular Genetics and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Mol Cancer Ther. 2004 Jan;3(1):71-84.
Resveratrol (trans-3,4,5-trihydroxystilbene) has received attention for its potential chemopreventive and antitumor effects in experimental systems. Recent evidence suggests that paclitaxel, alone or in combination with other drugs, can be effectively used in the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This study investigated whether resveratrol can sensitize NHL and MM cell lines to paclitaxel-mediated apoptosis and to delineate the underlying molecular mechanism of sensitization. Both resveratrol and paclitaxel negatively modulated tumor cell growth by arresting the cells at the G(2)-M phase of the cell cycle. Low concentrations of resveratrol exerted a sensitizing effect on drug-refractory NHL and MM cells to apoptosis induced by paclitaxel. Resveratrol selectively down-regulated the expression of antiapoptotic proteins Bcl-x(L) and myeloid cell differentiation factor-1 (Mcl-1) and up-regulated the expression of proapoptotic proteins Bax and apoptosis protease activating factor-1 (Apaf-1). Paclitaxel down-regulated the expression of Bcl-x(L), Mcl-1, and cellular inhibitor of apoptosis protein-1 antiapoptotic proteins and up-regulated Bid and Apaf-1. Combination treatment resulted in apoptosis through the formation of tBid, mitochondrial membrane depolarization, cytosolic release of cytochrome c and Smac/DIABLO, activation of the caspase cascade, and cleavage of poly(adenosine diphosphate-ribose) polymerase. Combination of resveratrol with paclitaxel had minimal cytotoxicity against quiescent and mitogenically stimulated human peripheral blood mononuclear cells. Inhibition of Bcl-x(L) expression by resveratrol was critical for chemosensitization and its functional impairment mimics resveratrol-mediated sensitization to paclitaxel-induced apoptosis. Inhibition of Bcl-x(L) expression by resveratrol was due to the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and diminished activator protein-1-dependent Bcl-x(L) expression. The findings by resveratrol were corroborated with inhibitors of the ERK1/2 pathway. This study demonstrates that in resistant NHL and MM cell lines resveratrol and paclitaxel selectively modify the expression of regulatory proteins in the apoptotic signaling pathway and the combination, via functional complementation, results in synergistic apoptotic activity.
白藜芦醇（反式 -3,4,5 - 三羟基芪）因其在实验系统中潜在的化学预防和抗肿瘤作用而受到关注。最近的证据表明，紫杉醇单独或与其他药物联合使用，可有效用于治疗非霍奇金淋巴瘤（NHL）和多发性骨髓瘤（MM）。本研究调查了白藜芦醇是否能使NHL和MM细胞系对紫杉醇介导的细胞凋亡敏感，并阐明其敏感化的潜在分子机制。白藜芦醇和紫杉醇均通过将细胞阻滞在细胞周期的G(2)-M期来负向调节肿瘤细胞生长。低浓度的白藜芦醇对耐药的NHL和MM细胞对紫杉醇诱导的凋亡产生致敏作用。白藜芦醇选择性地下调抗凋亡蛋白Bcl-x(L)和髓样细胞分化因子-1（Mcl-1）的表达，并上调促凋亡蛋白Bax和凋亡蛋白酶激活因子-1（Apaf-1）的表达。紫杉醇下调Bcl-x(L)、Mcl-1和凋亡蛋白细胞抑制剂-1等抗凋亡蛋白的表达，并上调Bid和Apaf-1的表达。联合治疗通过形成tBid、线粒体膜去极化、细胞色素c和Smac/DIABLO的胞质释放、半胱天冬酶级联反应的激活以及聚（二磷酸腺苷 - 核糖）聚合酶的裂解导致细胞凋亡。白藜芦醇与紫杉醇的联合对静止和有丝分裂原刺激的人外周血单核细胞具有最小的细胞毒性。白藜芦醇对Bcl-x(L)表达的抑制对于化学增敏至关重要，其功能受损模拟了白藜芦醇介导的对紫杉醇诱导凋亡的致敏作用。白藜芦醇对Bcl-x(L)表达的抑制是由于细胞外信号调节激酶1/2（ERK1/2）途径的抑制以及激活蛋白-1依赖性Bcl-x(L)表达的减少。白藜芦醇的研究结果得到了ERK1/2途径抑制剂的证实。本研究表明，在耐药的NHL和MM细胞系中，白藜芦醇和紫杉醇选择性地改变凋亡信号通路中调节蛋白的表达，并且通过功能互补，联合使用可产生协同凋亡活性。
