Protein phosphatase 2A inhibition and circumvention of cisplatin cross-resistance by novel TCM-platinum anticancer agents containing demethylcantharidin.
Novel TCM-platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, derived from integrating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety, possess anticancer and protein phosphatase 2A inhibition properties. The compounds are able to circumvent cisplatin resistance by apparently targeting the DNA repair mechanism. Novel isosteric analogues [Pt(C(9)H(10)O(4))(NH(2)R)(2)] A and B, devoid of PP2A-inhibitory activity, were found to suffer from an enhanced DNA repair and were cross-resistant to cisplatin. The results advocate a well-defined structure-activity requirement associating the PP2A-inhibiting demethylcantharidin with the circumvention of cisplatin cross-resistance demonstrated by TCM-Pt compounds 1-5.
To
Kenneth K W
KK
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, Hong Kong.
Wang
Xinning
X
Yu
Chun Wing
CW
Ho
Yee-Ping
YP
Au-Yeung
Steve C F
SC
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002193:Cantharidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000138:chemical synthesis; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008516:Medicine, Chinese Traditional; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; C464435:demethylcantharidin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002193:Cantharidin; D002945:Cisplatin