The PARP inhibitor olaparib enhances the cytotoxicity of combined gemcitabine, busulfan and melphalan in lymphoma cells

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Abstract
The combination of gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) is a promising regimen for autologous stem-cell transplantation (SCT) for lymphomas. To further improve the efficacy of [Gem + Bu + Mel], we added poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Ola). We hypothesized that Ola would inhibit the repair of damaged DNA caused by [Gem + Bu + Mel]. Exposure of J45.01 and Toledo cell lines to IC10–20 of individual drug inhibited proliferation by 6–16%; [Gem + Bu + Mel] by 20–27%; and [Gem + Bu + Mel + Ola] by 61–67%. The synergistic cytotoxicity of the four-drug combination may be attributed to activation of the DNA-damage response, inhibition of PARP activity and DNA repair, decreased mitochondrial membrane potential, increased production of reactive oxygen species, and activation of the SAPK/JNK stress signaling pathway, all of which may enhance apoptosis. Similar observations were obtained using mononuclear cells isolated from patients with T-cell lymphocytic leukemia. Our results provide a rationale for undertaking clinical trials of this drug combination for lymphoma patients undergoing SCT.
Funding Information
  • National Institutes of Health (CA016672)
  • Stephen L. and Lavinia Boyd

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