Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.
Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.
复制标题
3-溴丙酮酸与雷帕霉素在体内和体外结合增强的抗肿瘤活性。
DOI：
10.1158/1940-6207.capr-14-0142
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
You M
中科院分区：
文献类型：
--
作者：
Zhang Q;Pan J;Lubet RA;Komas SM;Kalyanaraman B;Wang Y;You M
3-溴丙酮酸（3-BrPA）是一种烷基化剂，也是一种众所周知的能量代谢抑制剂。雷帕霉素是一种丝氨酸/苏氨酸蛋白激酶“哺乳动物雷帕霉素靶蛋白（mTOR）”抑制剂。3-BrPA和雷帕霉素对小鼠肺癌模型均有化学预防作用。据报道，肺癌治疗药物的气溶胶递送是一种有效的递送途径，在人体中几乎没有全身分布。在这项研究中，我们评估了3-BrPA和雷帕霉素联合使用对雾化治疗小鼠肺癌的预防作用，与单独使用任何一种药物相比，通过测量肿瘤多样性和肿瘤负荷，我们发现了一种协同能力。通过监测血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，未发现肝毒性的证据。为了解其作用机制，采用人非小细胞肺癌（NSCLC）细胞系进行了体外实验。3-溴丙酮酸和雷帕霉素也协同抑制细胞增殖。雷帕霉素单独阻断mTOR信号通路，而3-溴丙酮酸没有增强这种作用。鉴于3-BrPA作为糖酵解抑制剂的已知作用，我们在体外研究了3-BrPA处理的非小细胞肺癌细胞线粒体生物能量学的变化。3-BrPA显著降低糖酵解活性，这可能是由于三磷酸腺苷（ATP）耗散和甘油醛-3-磷酸脱氢酶（GAPDH）表达减少所致。我们的研究结果表明，雷帕霉素增强了3-溴丙酮酸的抗肿瘤功效，并且mTOR信号和糖酵解的双重抑制可能是肺癌化学预防的有效治疗策略。
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the Serine/Threonine protein kinase “mammalian target of rapamycin (mTOR). Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-Bromopyruvate and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3- bromopyruvate did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-bromopyruvate, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.