A Multi-Mitochondrial Anticancer Agent that Selectively Kills Cancer Cells and Overcomes Drug Resistance

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• 作者：Prof. Dr. Yong Bo Peng ; Prof. Dr. Zi Long Zhao ; Dr. Teng Liu ; Prof. Dr. Guo Jian Xie ; Dr. Cheng Jin ; Dr. Tang Gang Deng ; Dr. Yang Sun ; Prof. Dr. Xiong Li ; Prof. Dr. Xiao Xiao Hu ; Prof. Dr. Xiao Bing Zhang ; Prof. Dr. Mao Ye and Prof. Dr. Wei Hong Tan
• 刊名：ChemMedChem
• 出版年：2017
• 出版时间：February 3, 2017
• 年：2017
• 卷：12
• 期：3
• 页码：250-256
• 全文大小：1690K
• ISSN：1860-7187

文摘

Mitochondria are double-membrane-bound organelles involved mainly in supplying cellular energy, but also play roles in signaling, cell differentiation, and cell death. Mitochondria are implicated in carcinogenesis, and therefore dozens of lethal signal transduction pathways converge on these organelles. Accordingly, mitochondria provide an alternative target for cancer management. In this study, F16, a drug that targets mitochondria, and chlorambucil (CBL), which is indicated for the treatment of selected human neoplastic diseases, were covalently linked, resulting in the synthesis of a multi-mitochondrial anticancer agent, FCBL. FCBL can associate with human serum albumin (HSA) to form an HSA–FCBL nanodrug, which selectively recognizes cancer cells, but not normal cells. Systematic investigations show that FCBL partially accumulates in cancer cell mitochondria to depolarize mitochondrial membrane potential (MMP), increase reactive oxygen species (ROS), and attack mitochondrial DNA (mtDNA). With this synergistic effect on multiple mitochondrial components, the nanodrug can effectively kill cancer cells and overcome multiple drug resistance. Furthermore, based on its therapeutic window, HSA–FCBL exhibits clinically significant differential cytotoxicity between normal and malignant cells. Finally, while drug dosage and drug resistance typically limit first-line mono-chemotherapy, HSA–FCBL, with its ability to compromise mitochondrial membrane integrity and damage mtDNA, is expected to overcome those limitations to become an ideal candidate for the treatment of neoplastic disease.