In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by novel traditional Chinese medicine-platinum anti-cancer agents.
Protein phosphatase 2A (PP2A) is a new target for platinum (Pt)-based cancer chemotherapeutic agents. A series of novel Pt complexes containing demethylcantharidin, a modified component of a traditional Chinese medicine (TCM), [Pt(C8H8O5)(NH2R)2] 1-5 have been shown to inhibit PP2A both in its purified form and in cell homogenates. In this study, the potential efficacy of compounds 1-5 in suppressing the growth of PP2A-highly expressed liver cancer was evaluated. The in vitro anti-proliferative activity of compounds 1-5 was investigated in human hepatocellular carcinoma (HCC) cell lines using the MTT assay. Compounds 1-5 were about 2-20 and 20-200 times more potent than cisplatin and carboplatin, respectively, in SK-Hep1 and HepG2 cells. The in vivo anti-tumor efficacies of 1-5 were evaluated in a s.c. inoculated SK-Hep1 xenograft model in nude mice. Compounds 1-5 demonstrated definite in vivo activity (giving rise to an optimal %T/C as low as 14.5%) without inducing undue toxicity, contrasting the lack of activity of cisplatin and carboplatin. In a cisplatin-resistant model established in vivo in human HCC, compounds 1-5 could still elicit the same level of tumor growth suppression as in the control tumors, demonstrating the circumvention of cisplatin cross-resistance. An acute toxicity study in ICR mice showed that compounds 1-5 are not nephrotoxic at LD10. The high potency of the novel TCM-Pt compounds against liver cancer and the minimal toxicity suggest that they have significant potential to be developed into useful Pt-based anti-tumor drugs.
To
Kenneth K W
KK
School of Pharmacy, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
Ho
Yee-Ping
YP
Au-Yeung
Steve C F
SC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D016190:Carboplatin / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008516:Medicine, Chinese Traditional; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; 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; D009944:Organoplatinum Compounds; D016190:Carboplatin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002945:Cisplatin