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Open AccessArticle

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

1
Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
2
Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1493; https://doi.org/10.3390/cancers11101493
Received: 18 August 2019 / Revised: 7 September 2019 / Accepted: 30 September 2019 / Published: 3 October 2019
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.
Keywords: myelodysplastic syndrome; chronic myelomonocytic leukemia; acute myeloid leukemia; talazoparib; APE1 inhibitor III; poly(ADP ribose) polymerase 1/2; apurinic/apyrimidinic endonuclease 1 myelodysplastic syndrome; chronic myelomonocytic leukemia; acute myeloid leukemia; talazoparib; APE1 inhibitor III; poly(ADP ribose) polymerase 1/2; apurinic/apyrimidinic endonuclease 1
MDPI and ACS Style

Kohl, V.; Flach, J.; Naumann, N.; Brendel, S.; Kleiner, H.; Weiss, C.; Seifarth, W.; Nowak, D.; Hofmann, W.-K.; Fabarius, A.; Popp, H.D. Antileukemic Efficacy in Vitro of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies. Cancers 2019, 11, 1493.

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