title: Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy.
abstract: DNA is the well-known molecular target of current platinum-based anticancer drugs; consequently, their clinical use is severely restricted by their systemic toxicities and drug resistance originating from non-selective DNA damage. Various strategies have been developed to circumvent the shortcomings of platinum-based chemotherapy but the inherent problem remains unsolved. Here we report that platinum pyrithione (PtPT), a chemically well-characterized synthetic complex of platinum, inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to multiple cancer cells than cisplatin, without showing discernible DNA damage both in vitro and in vivo. Moreover, unlike the classical proteasome inhibitor bortezomib/Velcade which inhibits the proteasome via blocking the peptidase activity of 20S proteasomes, PtPT primarily deactivates 26S proteasome-associated deubiquitinases USP14 and UCHL5. Furthermore, PtPT can selectively induce cytotoxicity and proteasome inhibition in cancer cells from leukemia patients but not peripheral blood mononuclear cells from healthy humans. In nude mice, PtPT also remarkably inhibited tumor xenograft growth, without showing the adverse effects that were induced by cisplatin. Hence, we have discovered a new platinum-based anti-tumor agent PtPT which targets 26S proteasome-associated deubiquitinases rather than DNA in the cell and thereby exerts safer and more potent anti-tumor effects, identifying a highly translatable new platinum-based anti-cancer strategy.
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.|Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Liao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Xianping
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, China.|Key Lab of Natural Drug and Immune Engineering of Henan Province, Kaifeng, Henan 475004, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong 510095, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.|Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms; D047368:Tumor Burden / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D061988:Proteasome Inhibitors; D011725:Pyridines; C509299:USP14 protein, human; C000618331:platinum pyrithione; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D002945:Cisplatin
keywords: DNA damage; Deubiquitinases; Platinum pyrithione; Proteasome; Tumor