Barbara Ann Karmanos Cancer Institute, Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201-2013, USA.
Int J Mol Med. 2012 Jan;29(1):102-6. doi: 10.3892/ijmm.2011.814. Epub 2011 Oct 13.
The proteasome plays a vital role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis and is a validated target in cancer treatment. Bortezomib (Velcade®, PS-341) is the first US FDA approved proteasome inhibitor anticancer drug used in the treatment of refractory multiple myeloma. In spite of its improved efficacy compared to alternative therapies, about 60% of patients do not respond to bortezomib due to the emergence of resistance. We hypothesized that novel small molecules could enhance the proteasome-inhibitory and anticancer activities of bortezomib in resistant multiple myeloma cells in vitro and in vivo. The dietary polyphenol curcumin has been shown to exert anti-cancer activity in several cancer cell lines, but the effects of curcumin in solid tumors have been modest primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Here we show that the water-soluble analog of curcumin #12, but not curcumin, in combination with bortezomib could enhance the proteasome-inhibitory effect in multiple myeloma cells. Furthermore, the sensitivity of the myeloma cells to cytotoxic killing in the presence of otherwise sublethal concentrations of bortezomib was enhanced by incubation with the curcumin analog #12. These findings justify further investigation into those combinations that may yield potential therapeutic benefit.
蛋白酶体在降解参与细胞周期、细胞增殖和凋亡等多种途径的蛋白质中起着至关重要的作用，是癌症治疗中的一个有效靶点。硼替佐米（万珂®，PS-341）是美国食品和药物管理局（FDA）批准的第一种用于治疗难治性多发性骨髓瘤的蛋白酶体抑制剂抗癌药物。尽管与其他治疗方法相比，它的疗效有所提高，但由于出现耐药性，约有 60%的患者对硼替佐米没有反应。我们假设，新型小分子可以增强硼替佐米在体外和体内耐药多发性骨髓瘤细胞中的蛋白酶体抑制和抗癌活性。膳食多酚姜黄素已被证明在几种癌细胞系中具有抗癌活性，但由于其在胃肠道以外的组织中水溶性差和生物利用度低，其在实体瘤中的作用有限。在这里，我们表明，姜黄素的水溶性类似物 #12（而不是姜黄素）与硼替佐米联合使用可以增强多发性骨髓瘤细胞中的蛋白酶体抑制作用。此外，在用硼替佐米的亚致死浓度孵育时，骨髓瘤细胞对细胞毒性杀伤的敏感性增强。这些发现证明了进一步研究这些组合的合理性，这些组合可能具有潜在的治疗益处。
