Augmentation of apoptosis by the combination of bleomycin with trifluoperazine in the presence of mutant p53

Gregory F. Sullivan, Adrienne Garcia-Welch, Eileen White, Stuart Lutzker, William N. Hait

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


A variety of anticalmodulin drugs can increase the cytotoxicity of bleomycin, a DNA damaging cancer chemotherapeutic. The combination has been shown to produce greater than expected DNA damage compared wot what was observed with either drug alone. Promising preclinical results led to Phase I and Phase II trials of trifluoperazine and bleomycin, which revealed activity in non-Hodgkin's lymphoma. Despite the unique activity of the combination, the mechanism underlying the DNA damaging effect remained poorly understood. In several systems, DNA damage leads to the induction of programmed cell death or apoptosis, which is characterized by interoligonucleosomal cleavage of DNA. To determine whether the activity of the combination of bleomycin with trifluoperazine was due to induction of apoptosis, we exposed L1210 leukemic lymphocytes to bleomycin in the presence or absence of trifluoperazine. The combination produced DNA laddering, cellular shrinkage, and chromatin condensation typical of programmed cell death. Cell cycle analyses revealed a blockade of cells in G2/M, suggesting the presence of mutant p53, which was confirmed by immunoanalysis. In addition, L1210 cells were found not to overexpress Bcl-2 in the presence or absence of drugs. These results indicate that the enhancement of bleomycin induced DNA damage by trifluoperazine is mediated, at least in part, through the induction of apoptosis.

Original languageEnglish (US)
Pages (from-to)19-26
Number of pages8
JournalJournal of Experimental Therapeutics and Oncology
Issue number1
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Cancer Research


  • Cancer chemotherapy
  • Cell cycle distribution
  • L1210 cells
  • Leukemia

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