Antileukemic Efficacy in Vitro of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies.

Kohl Kohl,Hofmann Hofmann,Kleiner Kleiner,Brendel Brendel,Nowak Nowak,Popp Popp,Weiss Weiss,Flach Flach,Fabarius Fabarius,Naumann Naumann,Seifarth Seifarth

doi:10.3390/cancers11101493

Abstract

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and base excision repair, respectively. Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, in primary CD34+ MDS/CMML cell samples (n = 8; 4 MDS and 4 CMML) and in primary CD34+ or CD34− AML cell samples (n = 18) in comparison to healthy CD34+ donor cell samples (n = 8). Strikingly, talazoparib and APE1 inhibitor III demonstrated critical antileukemic efficacy in selected MDS/CMML and AML cell samples. Low doses of talazoparib and APE1 inhibitor III further increased the cytotoxic efficacy of decitabine in MDS/CMML and AML cells. Moreover, low doses of APE1 inhibitor III increased the cytotoxic efficacy of talazoparib in MDS/CMML and AML cells. In summary, talazoparib and APE1 inhibitor III demonstrated substantial antileukemic efficacy as single agents, in combination with decitabine, and combined with each other. Hence, our findings support further investigation of these agents in sophisticated clinical trials.

Highlights

Survival of patients belonging to the unfavorable risk groups of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) is poor after standard antileukemic therapy [1,2,3,4,5]
Talazoparib is a potent inhibitor of PARP1, which is involved in single-strand break repair (SSB-R) and base excision repair (BER) [21]
The cytotoxic efficacy of talazoparib and apyrimidinic endonuclease 1 (APE1) inhibitor III was analyzed after 3 d of initial expansion followed by 3 d of treatment in CD34+ MDS/CMML cells (n = 8; 4 MDS and 4 CMML samples) and in CD34+ or CD34− AML cells (n = 18) in comparison to healthy CD34+ donor cells (n = 8) (Table 1, Figure 1)

Summary

Introduction

Survival of patients belonging to the unfavorable risk groups of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) is poor after standard antileukemic therapy [1,2,3,4,5]. Recent advances in the understanding of the biology of MDS/CMML and AML led to the development of novel targeted and untargeted agents (e.g., IDH inhibitors, FLT3 inhibitors, splicing modulators, novel DNMTi, anti-CD33 antibodies) [15,16,17,18,19,20]. In this context, inhibitors of poly(ADP-ribose) polymerase (PARP) 1/2 and apurinic/apyrimidinic endonuclease (APE) 1 may represent innovative. DNA repair inhibitors that target MDS/CMML and AML cells by inhibition of single-strand break repair (SSB-R) and base excision repair (BER), respectively.

Methods

Results

Discussion

Conclusion