Novel Therapeutics Laboratory, Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 02115, USA.
J Thorac Cardiovasc Surg. 2010 May;139(5):1233-40. doi: 10.1016/j.jtcvs.2009.06.027. Epub 2009 Oct 22.
Although platinum-based chemotherapy is widely used in malignant pleural mesothelioma, its modest therapeutic effect warrants identification of enhancing agents. As with many cancers, the phosphatidylinositol 3-kinase/Akt pathway is often activated in malignant pleural mesothelioma and has been implicated in the tumor's aggressiveness. Sirolimus is a well-established inhibitor of the mammalian target of rapamycin. We sought to determine whether combination treatment with sirolimus and cisplatin would enhance cell death in malignant pleural mesothelioma.
Human malignant pleural mesothelioma cell lines were incubated with sirolimus or cisplatin alone or in combination and assayed for cell viability. To characterize phosphorylation status after treatment, Akt and downstream proteins of mammalian target of rapamycin pathway, p70 S6 kinase and 4E-BP1, were analyzed by Western blot. Effect of combination treatment was also analyzed with extreme drug resistance assay in 12 human malignant pleural mesothelioma tumors with varying resistance to cisplatin.
Individual malignant pleural mesothelioma cell lines exhibited a range of sensitivities to each drug without correlation with subtype. Sirolimus and cisplatin significantly (P = .029) increased cell death versus either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1, and p70 S6 kinase. Cell proliferation was significantly decreased in tumors subjected to sirolimus and cisplatin versus cisplatin or sirolimus alone.
Sirolimus appears to enhance the cytotoxicity of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. These results provide a basis for the clinical evaluation of combined sirolimus and cisplatin chemotherapy in malignant pleural mesothelioma.
虽然基于铂的化疗广泛用于恶性胸膜间皮瘤，但疗效欠佳，需要寻找增强剂。与许多癌症一样，磷酸肌醇 3-激酶/蛋白激酶 B（Akt）通路在恶性胸膜间皮瘤中经常被激活，并与肿瘤的侵袭性有关。西罗莫司是哺乳动物雷帕霉素靶蛋白（mTOR）的一种成熟抑制剂。我们试图确定西罗莫司与顺铂联合治疗是否会增强恶性胸膜间皮瘤的细胞死亡。
单独或联合使用西罗莫司或顺铂孵育人恶性胸膜间皮瘤细胞系，并检测细胞活力。为了分析治疗后磷酸化状态，通过 Western blot 分析 Akt 和 mTOR 通路下游蛋白 p70 S6 激酶和 4E-BP1。还通过 12 例对顺铂耐药性不同的人恶性胸膜间皮瘤肿瘤的极端耐药性测定来分析联合治疗的效果。
单个恶性胸膜间皮瘤细胞系对每种药物的敏感性各不相同，与亚型无关。在 4 个细胞系中，西罗莫司和顺铂联合用药比单独用药显著（P =.029）增加细胞死亡。联合治疗导致 Akt、4E-BP1 和 p70 S6 激酶去磷酸化。与顺铂或西罗莫司单独用药相比，用西罗莫司和顺铂处理的肿瘤细胞增殖明显减少。
西罗莫司似乎通过 mTOR 通路增强了顺铂对恶性胸膜间皮瘤细胞系的细胞毒性。这些结果为临床评估恶性胸膜间皮瘤中西罗莫司联合顺铂化疗提供了依据。
