Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

J Med Chem. 2015 Nov 12;58(21):8387-401. doi: 10.1021/acs.jmedchem.5b00732. Epub 2015 Oct 27.

Abstract

Phosphaplatins, platinum(II) and platinum(IV) complexes coordinated to a pyrophosphate moiety, exhibit excellent antitumor activities against a variety of cancers. To determine whether phosphaplatins trigger resistance to treatment by engaging DNA damage repair genes, a yeast genome-wide fitness assay was used. Treatment of yeast cells with pyrodach-2 (D2) or pyrodach-4 (D4) revealed no particular sensitivity to nucleotide excision repair, homologous recombination repair, or postreplication repair when compared with platin control compounds. Also, TNF receptor superfamily member 6 (FAS) protein was overexpressed in phosphaplatin-treated ovarian tumor cells, and platinum colocalized with FAS protein in lipid rafts. An overactivation of sphingomyelinase (ASMase) was noted in the treated cells, indicating participation of an extrinsic apoptotic mechanism due to increased ceramide release. Our results indicate that DNA is not the target of phosphaplatins and accordingly, that phosphaplatins might not cause resistance to treatment. Activation of ASMase and FAS along with the colocalization of platinum with FAS in lipid rafts support an extrinsic apoptotic signaling mechanism that is mediated by phosphaplatins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • DNA / genetics
  • DNA Repair / drug effects*
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Models, Molecular
  • Organophosphorus Compounds / chemistry*
  • Organophosphorus Compounds / pharmacology
  • Organophosphorus Compounds / therapeutic use*
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovary / drug effects
  • Ovary / metabolism
  • Ovary / pathology
  • Sphingomyelin Phosphodiesterase / metabolism
  • fas Receptor / genetics

Substances

  • Antineoplastic Agents
  • Organophosphorus Compounds
  • Organoplatinum Compounds
  • fas Receptor
  • DNA
  • Sphingomyelin Phosphodiesterase