Gordon Gavin J, Mani Madhubalan, Maulik Gautam, Mukhopadhyay Lipi, Yeap Beow Y, Kindler Hedy L, Salgia Ravi, Sugarbaker David J, Bueno Raphael
The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA.
Cancer Chemother Pharmacol. 2008 Apr;61(4):549-58. doi: 10.1007/s00280-007-0500-1. Epub 2007 May 24.
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G(2)/M and G(1)/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM.
恶性胸膜间皮瘤（MPM）是一种对化疗耐药的高致死性肿瘤。硼替佐米是一种经美国食品药品监督管理局（FDA）批准的蛋白酶体抑制剂，目前正在多种肿瘤中进行临床研究，但尚未在MPM中进行广泛研究。在本报告中，我们确定了培养的MPM细胞对单独使用硼替佐米以及与顺铂或培美曲塞联合使用的生物学和分子反应。我们在生存研究中使用了四种MPM细胞系（MS589、H28、H2052、JMN）、一种正常间皮细胞系（HM3）和一种肺癌细胞系（H23），单独使用硼替佐米、顺铂和培美曲塞，并通过同时给药或改变给药顺序进行联合使用。我们确定了硼替佐米对细胞周期、细胞凋亡以及细胞周期蛋白p21/WAF1和p27/KIP1的表达以及凋亡相关蛋白IAP-1、IAP-2、survivin和XIAP的影响。硼替佐米对MPM细胞具有高度细胞毒性，并诱导G(2)/M期和G(1)/S期细胞周期停滞。在4种MPM细胞系中的3种中，细胞凋亡以浓度和时间依赖性方式增加。硼替佐米使p21/WAF1和IAP-1的蛋白水平稳定或升高，对p27/KIP1、IAP-2、XIAP和survivin的影响较小。在与顺铂的联合研究中，硼替佐米在高浓度时通常具有协同作用，在低浓度时具有拮抗作用。当在顺铂或培美曲塞之前给药时，硼替佐米以浓度依赖性方式增加了它们的细胞毒性。硼替佐米单独使用或与标准化疗联合使用可能会改善MPM患者的预后，但给药顺序可能很重要。本研究证明了对硼替佐米在MPM中进行进一步评估的合理性。
