title: Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells.
abstract: Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 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 hours (IC(50) = 171-443 μmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 μmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Lovejoy
authors.forename: Maria
authors.initials: M
authors.lastname: Serova
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Shahin
authors.initials: S
authors.lastname: Emami
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D012333:RNA, Messenger
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; C530333:cis-diammine(pyridine)chloroplatinum(II)