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A Multi‐Mitochondrial Anticancer Agent that Selectively Kills Cancer Cells and Overcomes Drug Resistance
Author(s) -
Peng Yong Bo,
Zhao Zi Long,
Liu Teng,
Xie Guo Jian,
Jin Cheng,
Deng Tang Gang,
Sun Yang,
Li Xiong,
Hu Xiao Xiao,
Zhang Xiao Bing,
Ye Mao,
Tan Wei Hong
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600538
Subject(s) - mitochondrion , cancer cell , biology , microbiology and biotechnology , programmed cell death , cell , organelle , cytotoxicity , carcinogenesis , cancer research , cancer , apoptosis , biochemistry , in vitro , genetics
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.