There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
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 0.82μM 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 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.