Artemisinins Enhanced The Antileukemic Efficacy Of Bcl2 Inhibitors

Abstract More effective, less toxic treatments are needed to improve longevity and quality of life for patients with acute leukemias. Artesunate (AS), the current WHO-recommended drug for severe malaria, is a semi-synthetic derivative of the natural compound Artemisinin. AS has broad antineoplastic activity in vitro, and is well tolerated, inexpensive, and can be parenterally or orally administered in humans. Both AS and a more potent synthetic derivative, artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838), substantially inhibited acute leukemia growth in vivo and in vitro, at doses where normal CD34+ hematopoietic stem-progenitor cell clonogenicity was essentially unaffected. Moreover, AS and ART-838 synergized with several current antileukemic drugs (Fox et al, Oncotarget, 2015). To identify additional potential antileukemic drug combinations, we screened for the growth inhibitory effects of AS and ART-838 against 3 acute leukemia cell lines co-treated with a panel of 122 antileukemic compounds (mainly emerging antineoplastic drugs). Both AS and ART-838 showed synergistic or additive growth inhibition with several compounds. Two BCL2 protein family inhibitors demonstrated among the highest levels of synergy. One of these, ABT-199 (venetoclax), was recently approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL) and received breakthrough designation for acute myeloid leukemia (AML). Therefore, we decided to further investigate the combination of ABT-199 with AS or ART-838. Synergy between AS (or ART-838) and ABT-199 was confirmed across several acute leukemia cell lines with varying sensitivities to each drug. Both leukemia cell proliferation and survival were affected synergistically by exposure to the combination of AS (or ART-838) plus ABT-199. Utilizing in vivo imaging, we assessed changes in growth kinetics of tail vein-injected acute leukemia cell lines and primary patient-derived samples constitutively expressing luciferase in mice treated with AS, ABT-199, or the combination. The combination of AS plus ABT-199 had the greatest antileukemic effect. Based on these data, we propose that Artemisinins plus BCL2 inhibitors comprise an antileukemic drug pair with high potential for incorporation into acute leukemia therapeutic regimens. Citation Format: Blake S. Moses, Jennifer M. Fox, Xiaochun Chen, Jeffrey W. Tyner, Gary H. Posner, Patrick Bailey, Curt I. Civin. Artemisinins enhanced the antileukemic efficacy of BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2023. doi:10.1158/1538-7445.AM2017-2023