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

Abstract

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.

• Authors: Yong Bo Peng, Zi Long Zhao, Teng Liu, Guo Jian Xie, Cheng Jin, Tang Gang Deng, Yang Sun, Xiong Li, Xiao Xiao Hu, Xiao Bing Zhang, Mao Ye, Wei Hong Tan
• Journal: ChemMedChem (ChemMedChem) Vol. 12 Issue 3 Pg. 250-256 (02 03 2017) ISSN: 1860-7187 [Electronic] Germany
• PMID: 28098432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• DNA, Mitochondrial
• Chlorambucil

Topics

• Antineoplastic Agents (chemistry, toxicity)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chlorambucil (chemistry, toxicity)
• DNA Damage (drug effects)
• DNA, Mitochondrial (chemistry, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• HeLa Cells
• Humans
• Microscopy, Confocal
• Mitochondria (drug effects, metabolism)