顺铂（Cisplatin，[cis-diaminodichloroplatinum (II) (CDDP)]）是10年来临床使用的最常见抗癌药物之一，但是这种药物具有较明显的消化道及肾毒性，因此使用受到很大的限制。来自南京医科大学癌症中心，第三军医大学附属新桥医院（Xinqiao Hospital）呼吸道疾病研究院，中科院上海生科院营养科学研究院，以及美国西维吉尼亚大学的研究人员发现顺铂CDDP与AKT1的生物学关联，为获得性CDDP抗性提出了一个新机制，以及一种新的潜在克服癌症治疗中CDDP抗性的治疗靶标。这一研究成果公布在Cancer Research杂志上。
文章的通讯作者是来自南京医科大学的蒋兵华（Bing-Hua Jiang，音译），其它还包括第三军医大学新桥医院全军呼吸内科研究所所长钱桂生教授，上海营养所史香林等。
以上的研究表明AKT扩增和雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR，另一实验证明）途径在人类肺癌细胞的获得性CDDP抗性的产生过程中扮演着关键的角色，为获得性CDDP抗性提出了一个新机制，以及一种新的潜在克服癌症治疗中CDDP抗性的治疗靶标。
在之前的研究中，维吉尼亚大学的研究人员也发现顺铂在肾脏内被激活，通过活化卤化烯烃相同的途径代谢为毒性代谢产物。随着谷胱甘肽共轭物的形成，顺铂被激活。谷胱甘肽共轭物被代谢为半胱氨酰－甘氨酸共轭物、半胱氨酸共轭物，最后形成一反应性硫醇。
在这项研究中，科研人员将融合的单层LLC-PK(1)细胞与临床浓度相当的顺铂或顺铂共轭物接触3小时。在72小时测定细胞的存活性。他们观察了γ－谷氨酰转肽酶（GGT）和半胱氨酸-S共轭物β-裂解酶在顺铂共轭物代谢中的作用。他们预先将顺铂与谷胱甘肽、半胱氨酰－甘氨酸或N－乙酰－半胱氨酸培养，促使顺铂裂解酶的自发形成，从而增加顺铂对LLC-PK(1)细胞的毒性。
对GGT活性的抑制研究表明，GGT是顺铂－谷胱甘肽共轭物毒性所必需的。抑制半胱氨酸-S共轭物β-裂解酶的活性可减少各种顺铂共轭物的毒性。这些资料表明顺铂在肾近端小管细胞的代谢是其肾毒性的基础。这一通路的阐明将为抑制顺铂肾毒性提供新的靶点。
原始出处：
Cancer Research 67, 6325-6332, July 1, 2007. doi: 10.1158/0008-5472.CAN-06-4261
Experimental Therapeutics, Molecular Targets, and Chemical Biology
AKT1 Amplification Regulates Cisplatin Resistance in Human Lung Cancer Cells through the Mammalian Target of Rapamycin/p70S6K1 Pathway
Ling-Zhi Liu1, Xiang-Dong Zhou2,3, Guisheng Qian2, Xianglin Shi4, Jing Fang4 and Bing-Hua Jiang1,5
1 Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China; 2 Institute of Respiratory Diseases, Xinqiao Hospital and 3 Department of Respiratory Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China; 4 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and 5 Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia
Requests for reprints: Bing-Hua Jiang, Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu, China. E-mail: bhjiang@njmu.edu.cn .
Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is one of the most widely used and effective therapeutic agents for many kinds of cancers. However, its efficiency is limited due to development of drug resistance. In this study, we showed that CDDP resistance was associated with AKT1 overexpression and gene amplification in human lung cancer cells that acquired the drug resistance. We showed that AKT1 forced expression in the cells was sufficient to render the cells CDDP resistant, and that AKT1 inhibition by its dominant negative mutant reversed the CDDP-resistant cells to be CDDP sensitive. These results show that AKT1 activity is essential for regulating CDDP resistance in cultured lung cancer cells. To study whether these results were correlated with human lung cancer tumors, we randomly selected tumor samples from human lung cancer patients to study the correlation of AKT activation and CDDP resistance in clinical tumor samples. We showed that AKT activation was highly related to CDDP chemosensitivity in human tumor tissues. Our results further showed that AKT1 induced lung cancer cells to become resistant to CDDP through the mammalian target of the rapamycin (mTOR) signaling pathway. These studies conclude that AKT amplification and the mTOR pathway play an important role in human lung cancer cells acquiring CDDP resistance, which represents a new mechanism for acquiring CDDP resistance and a potential novel therapeutic target for overcoming CDDP resistance in human cancer in the future. [Cancer Res 2007;67(13):6325–32]
