Chemotherapeutic-induced apoptosis: A phenotype for pharmacogenomics studies

Yujia Wen, Lidija K. Gorsic, Heather E. Wheeler, Dana M. Ziliak, Rong Stephanie Huang, Mary Eileen Dolan

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

AIM: To determine whether cellular apoptosis is a suitable phenotypic trait for pharmacogenomics studies by evaluating caspase 3/7-mediated activity in lymphoblastoid cell lines after treatment with six chemotherapeutic agents: 5′-deoxyfluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin, and cisplatin. Materials and Methods: Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase 3/7 activity in lymphoblastoid cell lines. Genome-wide association studies were performed with over 2 million single nucleotide polymorphisms (SNPs) and cisplatin-induced apoptosis in HapMap CEU cell lines (n=77). Results: Although treatment with 5′-deoxyfluorouridine and pemetrexed for up to 24 h resulted in low levels of apoptosis or interindividual variation in caspase-dependent cell death; paclitaxel, cisplatin, carboplatin, and cytarabine treatment for 24 h resulted in 9.4-fold, 9.1-fold, 7.0-fold, and 6.0-fold increases in apoptosis relative to control, respectively. There was a weak correlation between caspase activity and cytotoxicity (r=0.03-0.29) demonstrating that cytotoxicity and apoptosis are two distinct phenotypes that may produce independent genetic associations. Estimated heritability (h) for apoptosis was 0.57 and 0.29 for cytarabine (5 and 40 μmol/l, respectively), 0.22 for paclitaxel (12.5 nmol/l), and 0.34 for cisplatin (5 μmol/l). In the genome-wide association study using the HapMap CEU panel, we identified a significant enrichment of cisplatin-induced cytotoxicity SNPs within the significant cisplatin-induced apoptosis SNPs and an enrichment of expression quantitative trait loci (eQTL). Among these eQTLs, we identified several eQTLs with known function related to apoptosis and/or cytotoxicity. Conclusion: Our study identifies apoptosis as a phenotype for pharmacogenomic studies in lymphoblastoid cell lines after treatment with paclitaxel, cisplatin, carboplatin, and cytarabine that may have utility for discovering biomarkers to predict response to certain chemotherapeutics.

Original languageEnglish (US)
Pages (from-to)476-488
Number of pages13
JournalPharmacogenetics and genomics
Volume21
Issue number8
DOIs
StatePublished - Aug 2011

Keywords

  • apoptosis
  • caspase 3/7
  • genome-wide association study
  • lymphoblastoid cell lines
  • toxicity

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