Cytotoxicity of anticancer drugs and PJ-34 (poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor) on HL-60 and Jurkat cells.

Abstract

The majority of the clinical trials with poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors were conducted or are ongoing in patients with solid tumors, while trials with leukemia patients are less frequent. Surprisingly scarce data is available on the combinatory effects of PARP inhibitors with DNA damaging antitumor drugs in leukemic cells (primary cells or established lines). The aim of the present study was to assess the effect of PJ-34 (PARP-1 inhibitor) on the cytotoxicity of different antileukemic drugs with different DNA damaging mechanisms and potency (doxorubicin, etoposide, cytarabine and chlorambucil) in human leukemic Jurkat and HL-60 cells. Different exposure scenarios were applied: 1) 72 h simultaneous incubation with PJ-34 (2.5 or 5 μM for Jurkat and HL-60 cells, respectively) and a drug used at a wide concentration range; 2) preincubation of the cells with PJ-34 for 24 h and then with a combination of PJ-34 + drug for an additional 48 h; 3) preincubation of the cells with the drug for 24 h with a subsequent incubation with a combination of PJ-34 + drug for an additional 48 h. Cytotoxicity was assessed using a WST-1 reduction test. It was determined that PJ-34, when used in all 3 scenarios, did not induce any significant enhancement of cytotoxicity of the drugs either in Jurkat or in HL-60 cells. Although the results do not confirm the beneficial effects of PARP inhibition in combination treatment of the leukemic cells, we propose that future studies including an additional step with the inhibition of DNA repair by homologous recombination should provide promising results.