ANTICANCER ACTIVITY OF PYRIPLATIN, A MONOFUNCTIONAL CATIONIC PLATINUM(II) COMPOUND, IN HUMAN CANCER CELLS

Abstract

Pyriplatin (cis-diammine(pyridine)chloroplatinum(II) or cDPCP), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for the organic cation transporters, hOCT1 and hOCT2, which facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, as well as combintions of pyriplatin with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin or 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 h (IC50: 171 – 443 μM), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 h (IC50: 24 μM). Pyriplatin caused a G2/M block of cell cycle similar to that induced by cisplatin and oxaliplatin. Apoptotic cell death was supported by Annexin-V analysis and detection of phosphorylated H2AX and Chk2. Treatment with pyriplatin caused an increase in CDKN1/p21 and decrease in ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin adducts resulted in less cytotoxicity than cisplatin- and oxaliplatin-DNA adducts. The mRNA levels of several genes implicated in drug transport and repair of DNA damage, including MSH2 and GSTP1, correlate with pyriplatin cellular activity in our panel of cell lines. Synergy was observed in combinations of pyriplatin with paclitaxel. Because it has a different spectrum of activitythan that of cisplatin or oxaliplatin, pyriplatin may be regarded as a lead compound for the development of other drug candidates with cytotoxicity profiles that differ from those of the drugs currently in use.