順鉑（Cisplatin,，[cis-diaminodichloroplatinum (II) (CDDP)]）是10年來臨床使用的最常見抗癌藥物之一,，但是這種藥物具有較明顯的消化道及腎毒性,，因此使用受到很大的限制,。來自南京醫(yī)科大學癌癥中心，第三軍醫(yī)大學附屬新橋醫(yī)院（Xinqiao Hospital）呼吸道疾病研究院,，中科院上海生科院營養(yǎng)科學研究院,，以及美國西維吉尼亞大學的研究人員發(fā)現(xiàn)順鉑CDDP與AKT1的生物學關(guān)聯(lián)，為獲得性CDDP抗性提出了一個新機制,，以及一種新的潛在克服癌癥治療中CDDP抗性的治療靶標,。這一研究成果公布在Cancer Research雜志上。
文章的通訊作者是來自南京醫(yī)科大學的蔣兵華（Bing-Hua Jiang,，音譯）,，其它還包括第三軍醫(yī)大學新橋醫(yī)院全軍呼吸內(nèi)科研究所所長錢桂生教授，上海營養(yǎng)所史香林等,。
以上的研究表明AKT擴增和雷帕霉素靶蛋白（mammalian target of rapamycin,，mTOR，另一實驗證明）途徑在人類肺癌細胞的獲得性CDDP抗性的產(chǎn)生過程中扮演著關(guān)鍵的角色,，為獲得性CDDP抗性提出了一個新機制,，以及一種新的潛在克服癌癥治療中CDDP抗性的治療靶標。
在之前的研究中,，維吉尼亞大學的研究人員也發(fā)現(xiàn)順鉑在腎臟內(nèi)被激活,，通過活化鹵化烯烴相同的途徑代謝為毒性代謝產(chǎn)物。隨著谷胱甘肽共軛物的形成,，順鉑被激活,。谷胱甘肽共軛物被代謝為半胱氨酰－甘氨酸共軛物、半胱氨酸共軛物,，最后形成一反應(yīng)性硫醇,。
在這項研究中，科研人員將融合的單層LLC-PK(1)細胞與臨床濃度相當?shù)捻樸K或順鉑共軛物接觸3小時,。在72小時測定細胞的存活性,。他們觀察了γ－谷氨酰轉(zhuǎn)肽酶（GGT）和半胱氨酸-S共軛物β-裂解酶在順鉑共軛物代謝中的作用。他們預先將順鉑與谷胱甘肽,、半胱氨酰－甘氨酸或N－乙酰－半胱氨酸培養(yǎng),，促使順鉑裂解酶的自發(fā)形成，從而增加順鉑對LLC-PK(1)細胞的毒性,。
對GGT活性的抑制研究表明,，GGT是順鉑－谷胱甘肽共軛物毒性所必需的。抑制半胱氨酸-S共軛物β-裂解酶的活性可減少各種順鉑共軛物的毒性,。這些資料表明順鉑在腎近端小管細胞的代謝是其腎毒性的基礎(chǔ),。這一通路的闡明將為抑制順鉑腎毒性提供新的靶點。
原始出處：
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: [email protected] .
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]
