Platinum drug effects on the expression of genes in the polyamine pathway: Time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells

Ram Varma, Suzanne Hector, William R. Greco, Kimberly Clark, Lesleyann Hawthorn, Carl Porter, Lakshmi Pendyala

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Purpose: As a follow-up to our previous findings that platinum drugs induce a key enzyme in polyamine catabolism, gene expression profiling and mathematical modeling were used to define the effects of cisplatin and oxaliplatin on the expression of polyamine metabolic pathway genes in A2780 human ovarian carcinoma cells. Methods: Time-course and concentration-effect experiments were each carried out with cisplatin or oxaliplatin in two separate experiments and cells subjected to gene expression profiling using Affymetrix array technology. Time-course data were modeled using exponential increase and decrease models. Concentration-effect data were modeled using a four parameter Hill model. Results: Gene expression profiling of human ovarian carcinoma A2780 cells after exposure to either cisplatin or oxaliplatin indicates that the expression of several genes involved in polyamine pathway is affected by the platinum drugs. Mathematical/Statistical modeling of the data from time-course and concentration-effect experiments of gene expression from nine polyamine pathway genes represented on the HGU95Av2 chip, indicates that three biosynthetic pathway genes (SAMDC, ODC1 and SRM) are down-regulated and one catabolic pathway gene (SSAT) is up-regulated. Expression changes were similar for different probesets for a given gene on the array. Studies on the induction of SSAT by platinum drugs suggested by the Affymetrix data have been previously validated from this laboratory (Hector et al. in Mol Cancer Ther 3:813-822, 2004). Here, the effects of oxaliplatin exposure on SAMDC and ODC observed by Affymetix are validated with real time QRT-PCR. Conclusion: The data indicate a concerted effect of platinum drugs on the polyamine metabolic pathway with down-regulation in the expression of several enzyme genes involved in biosynthesis and many-fold up-regulation in expression of SSAT, an acetylating enzyme gene that is critically involved in polyamine catabolism and export.

Original languageEnglish (US)
Pages (from-to)711-723
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume59
Issue number6
DOIs
StatePublished - Jun 2007
Externally publishedYes

Keywords

  • Cisplatin
  • Gene expression profiling
  • Oxaliplatin
  • Platinum
  • Polyamines

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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