Abstract 818: Repurposing Artemisinins for treatment of acute leukemias
Authors: Jennifer M. Fox, James R. Moynihan, Gary H. Posner, Patrick Brown, Curt I. Civin, Xiaochun Chen
Journal: Cancer Research (2014)

Abstract More effective, less toxic treatments are needed to improve quantitative and qualitative outcomes for patients with acute leukemias. Drug repurposing has been validated as a productive approach in which the pharmacologic and safety information available for established drugs promotes their rapid translation to human clinical trials for a new indication. Artesunate (ART), the current WHO-recommended drug for severe malaria, is a semi-synthetic derivative of the natural compound Artemisinin. ART has broad anti-cancer activity in vitro, and is inexpensive, safe, and can be parenterally or orally administered in humans. We sought to characterize the anti-leukemic activity of ART and ART-838 (a novel potent analog) and to evaluate these drugs in combination with several current and emerging anti-leukemic drugs. We assessed the growth inhibitory effects of ART and ART-838 against a panel of 24 acute leukemia (Acute Myeloid Leukemia [AML], Precursor B cell Acute Lymphoblastic Leukemia [B-ALL], and T cell ALL) cell lines via alamarBlue assays. Both ART (mean IC50: 5.4 μM; median IC50: 4.1 μM) and ART-838 (mean IC50: 0.12 μM; median IC50: 0.06 μM) were active against all 24 cell lines, indicating efficacy against the major types of acute leukemia. Primary leukemia cases, grown on hTERT-immortalized bone marrow stromal cells, were sensitive over a similar concentration range. Both ART (≤10 μM) and ART-838 (≤0.25 μM) reduced or completely inhibited clonigenicity of all 4 acute leukemia cell lines tested in methylcellulose colony-forming assays. In contrast, clonigenicity of normal CD34+ hematopoietic stem-progenitor cells was unaffected by concentrations of ART and ART-838 that inhibited all tested acute leukemia cell lines and primary cases, suggesting high therapeutic indices. ART exhibited additive or synergistic interactions with several anti-neoplastic agents (including Cytarabine, Doxorubicin, Etoposide, Lestaurtinib, Midostaurin, and Sorafenib) against KOPN8 (B-ALL), MOLM14 (AML), and MV4;11 (biphenotypic AML/B-ALL) leukemia cell lines, suggesting the potential for successful integration of ART or ART-838 into existing or novel combination chemotherapy regimens. 24h treatment with ART or ART-838 caused a marked reduction in BrdU-labeled S-phase cells and a large increase in Annexin-V positive (apoptotic) cells. Finally, both ART and ART-838 inhibited leukemia development in immunodeficient NSG mice transplanted with KOPN8 cells. Based on these data, we propose that ART and ART-838 have high potential to be developed as anti-leukemic agents that could be paired with current standard and/or novel anti-leukemic drugs. Citation Format: Jennifer M. Fox, James R. Moynihan, Gary H. Posner, Patrick Brown, Curt I. Civin, Xiaochun Chen. Repurposing Artemisinins for treatment of acute leukemias. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 818. doi:10.1158/1538-7445.AM2014-818