Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain.
To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University , Guilin, Guangxi, China.
Yi
Y
Gou
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University , Guilin, Guangxi, China.
Jinxu
J
Qi
Ben May Department for Cancer Research, University of Chicago , Chicago, Illinois 60637, United States.
Joshua-Paul
JP
Ajayi
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University , Guilin, Guangxi, China.
Yao
Y
Zhang
Guangxi Universities Key Laboratory of Stem Cell and Pharmaceutical Biotechnology, Guangxi Normal University , Guilin, Guangxi, China.
Zuping
Z
Zhou
Ben May Department for Cancer Research, University of Chicago , Chicago, Illinois 60637, United States.
Xiaoyang
X
Wu
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University , Guilin, Guangxi, China.
Feng
F
Yang
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University , Guilin, Guangxi, China.
Hong
H
Liang
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003300:Copper / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000970:Antineoplastic Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species; D012709:Serum Albumin; D003300:Copper
anticancer activity; anticancer mechanism; drug delivery systems; human serum albumin; pro-drug