Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models.
Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models.
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DOI：
10.1158/1535-7163.mct-08-0534
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发表时间：
2009-02
影响因子：
5.7
通讯作者：
Eckhardt SG
中科院分区：
文献类型：
--
作者：
Pitts TM;Morrow M;Kaufman SA;Tentler JJ;Eckhardt SG
尽管有几种食品和药物管理局批准的药物，晚期不可手术的结直肠癌仍然无法治愈。在这项研究中，我们专注于开发针对结肠癌的联合分子靶向治疗，通过测试组蛋白脱乙酰酶抑制剂伏立诺他与蛋白酶体抑制剂硼替佐米的组合的疗效，以确定这是否会导致对结直肠癌的协同抗肿瘤作用。组蛋白去乙酰化酶抑制剂伏立诺他与蛋白酶体抑制剂硼替佐米组合对两种结直肠癌细胞系的生长的影响在增殖、细胞周期停滞和凋亡方面进行了评估。与单独使用单药治疗相比，伏立诺他和硼替佐米联合治疗导致两种结直肠癌细胞系增殖的协同降低。这种抑制与细胞凋亡的协同增加相关，如通过caspase-3/7活性和裂解的聚（ADP-核糖）聚合酶所测量的。此外，我们观察到促凋亡蛋白BIM和细胞周期G2-M期阻滞的细胞数量增加。尽管p21水平显著增加，但p21的短发夹RNA敲低并没有导致对药物组合的响应的增殖变化，这表明尽管p21是这些药物的靶点，但不需要介导它们的抗增殖作用。这些数据表明，伏立诺他和硼替佐米的组合治疗导致针对结肠癌细胞系的协同抗增殖和促凋亡作用，为该组合用于治疗结肠直肠癌的临床用途提供了合理的基础。
Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G2-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer.