General AML

Antileukemic activity of artesunate (antimalarial agent) in AML

Artemisinins are a family of antimalarial compounds whose activity is facilitated by the generation of Reactive Oxygen Species (ROS).

The antineoplastic activity and mechanism of action of artemisinins, in particular Artesunate (ARTS), in Acute Myeloid Leukemia (AML) was investigated by Bijender Kumar and colleagues from City of Hope Medical Center, Duarte, CA, USA. The results were published in Leukemia Research on 12th May 2017.

Using Fms Like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) positive AML cell lines, MV4-11 and MOLM-13, the authors investigated the anti-proliferative activity and cytotoxicity of ARTS in vitro.

The key results of the study were:  
  • ARTS in combination with doxorubicin or cytarabine significantly increased the apoptosis rates of MV4-11 and MOLM-13 cells compared to daunorubicin or cytarabine alone
  • ARTS significantly augmented the cytotoxicity of doxorubicin or cytarabine in primary CD34+ patient blasts
  • Treatment of MV4-11 cells with ARTS and N-acteyl cysteine treatment resulted in the attenuation of cytotoxicity of ARTS against MV4-11 cells
  • Treatment of MV4-11 cells with ARTS led to an increase in mitochondrial ROS, DNA damage and an induction of C-Jun N- terminal kinase (JNK), a mediator of apoptosis
  • Compared to control, ARTS significantly reduced BCL-2 (an anti-apoptotic protein) in MV4-11 and MOLM-13 cells
  • There was a significant increase in apoptosis of MOLM-11 cells when they were treated with ARTS in combination with ABT-199 (venetoclax, a BCL-2 inhibitor) compared to ABT-199 alone; 47.4 ± 2.1% vs 21.5 ± 1.2%, P = 0.007

The authors also investigated the in vivo activity of ARTS in an AML mouse model.

The key results were:
  • Treatment of mice engrafted with MLL-AF9 knock-in cells with ARTS, led to a significant reduction in splenomegaly and prolongation of survival duration
  • Median survival of NGS mice injected with patient derived FLT3-ITD+ AML cells treated with ARTS compared to control; 35 vs 39 days, P = 0.012
  • Median survival of NGS mice injected with MV4-11 cells treated with ARTS and cytarabine compared to ARTS alone; 45 vs 38 days, P = 0.0023

 In summary, ARTS has a potent antileukemic activity in AML, which is mediated by the induction of ROS. Additionally, ARTS augments the cytotoxicity of chemotherapy and ABT-199.

The authors concluded by suggesting that their results support the use of ARTS in combination with standard chemotherapy or venetoclax in clinical studies in patients with AML.

 Abstract

The artimisinins are a class of antimalarial compounds whose antiparasitic activity is mediated by induction of reactive oxygen species (ROS). Herein, we report that among the artimisinins, artesunate (ARTS), an orally bioavailable compound has the most potent antileukemic activity in AML models and primary patients’ blasts. ARTS was most cytotoxic to the FLT3-ITD+ AML MV4-11 and MOLM-13 cells (IC50 values of 1.1 and 0.82 μM respectively), inhibited colony formation in primary AML and MDS cells and augmented cytotoxicity of chemotherapeutics. ARTS lowered cellular BCL-2 level via ROS induction and increased the cytotoxicity of the BCL-2 inhibitor venetoclax (ABT-199). ARTS treatment led to cellular and mitochondrial ROS accumulation, double stranded DNA damage, loss of mitochondrial membrane potential and induction of the intrinsic mitochondrial apoptotic cascade in AML cell lines. The antileukemic activity of ARTS was further confirmed in MV4-11 and FLT3-ITD+ primary AML cell xenografts as well as MLL-AF9 syngeneic murine AML model where ARTS treatment resulted in significant survival prolongation of treated mice (P = 0.012 for the FLT3-ITD xenograft model) compared to control. Our results demonstrate the potent preclinical antileukemic activity of ARTS as well as its potential for a rapid transition to a clinical trial either alone or in combination with conventional chemotherapy or BCL-2 inhibitor, for treatment of AML.

References
  1. Kumar B. et al. Antileukemic activity and cellular effects of the antimalarial agent artesunate in acute myeloid leukemia. Leuk Res. 2017 May. DOI: 10.1016/j.leukres.2017.05.007. [Epub ahead of print].