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.
Potential conflict of interest
Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2017.1306647.