Poly(ADP-Ribose) Polymerase Inhibitors for Arsenic Trioxide–Resistant Acute Promyelocytic Leukemia: Synergistic In Vitro Antitumor Effects with Hypomethylating Agents or High-Dose Vitamin C

Abstract

Arsenic trioxide (ATO) is an anticancer agent used for the treatment of acute promyelocytic leukemia (APL). However, 5-10% of patients fail to respond or experience disease relapse. Based on poly(ADP-ribose) polymerase 1 (PARP1) involvement in the processing of DNA demethylation, here we have tested the in vitro susceptibility of ATO-resistant clones, derived from the human APL cell line NB4, to PARP inhibitors (PARPi) in combination with hypomethylating agents (azacitidine and decitabine) or high-dose vitamin C (ascorbate), which induces 5hydroxymethylcytosine (5hmC)-mediated DNA demethylation. ATO-sensitive andresistant APL cell clones were generated and initially analyzed for their susceptibility to five clinically used PARPi (olaparib, niraparib, rucaparib, veliparib and talazoparib).The obtained PARPi IC 50 values were far below (olaparib and niraparib), within the range (talazoparib) or above (rucaparib and veliparib) the Cmax reported in patients, likely due to differences in the mechanisms of their cytotoxic activity. ATO-resistant APL cells were also susceptible to clinically relevant concentrations of azacitidine and decitabine and to high-dose ascorbate. Interestingly, the combination of these agents with olaparib, niraparib or talazoparib resulted in synergistic antitumor activity.In combination with ascorbate, PARPi increased the ascorbate-mediated induction of 5hmC, which likely resulted in stalled DNA repair and cytotoxicity. Talazoparib was the most effective PARPi in synergizing with ascorbate, in accordance with its marked ability to trap PARP1 at damaged DNA. These findings suggest that ATO and PARPi have non-overlapping resistance mechanisms and support further investigation on PARPi combination with hypomethylating agents or high-dose ascorbate for relapsed/ATO-refractory APL especially in frail patients.

Epigenetic Insights on PARP-1 Activity in Cancer Therapy

“…Similar results on the efficacy of PARPi and hypomethylating agents were also demonstrated in AML and breast cancer [90,91]. Furthermore, different types of PARPi showed promising therapeutic effects for treating arsenic trioxide-acute promyelocytic leukaemia (APL) in combination with DNMTi or high-dose ascorbate that is shown to increase 5hmC and thus the DNA demethylating ability of TET enzymes [92].…”

Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance

“…Particularly, PARP14 can promote glycolysis in different tumor models, such as human hepatocellular carcinoma (HCC), by maintaining reduced PKM2 activity (Iansante et al, 2015); on the other hand, a close relationship between c-myc and AKT has been reported in B lymphomas (Cho et al, 2011) and AML through the NF-κB/HIF-1α axis (Zhu et al, 2022). Interestingly, the use of Niraparib, a PARP1/2 inhibitor, decreases resistance to ATO and hypomethylating agents (azacytidine and decitabine) in tumor promyelocytes (Giansanti et al, 2021).…”

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

“…Few studies are available on the efficacy of niraparib in acute leukemias. Niraparib, as well as other PARPs inhibitors, was effective against arsenic trioxide (ATO)-resistant acute promyelocytic leukemia (APL) primary cells alone and in combination with hypomethylating agents (azacitidine and decitabine) or high-dose vitamin C (ascorbate) [ 111 ]. The synergism was dependent on the role of PARP1 protein in the processing of DNA demethylation.…”