TY - JOUR
T1 - MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML
AU - Carter, B. Z.
AU - Mak, D. H.
AU - Shi, Y.
AU - Fidler, J. M.
AU - Chen, R.
AU - Ling, X.
AU - Plunkett, W.
AU - Andreeff, M.
N1 - Funding Information:
We thank Kate J Newberry and Deanna A Alexander for helping with the manuscript preparation. This work was supported in part by grants from the National Institutes of Health (P01 CA055164 and MD Anderson’s Cancer Center Support Grant CA016672) and by the Paul and Mary Haas Chair in Genetics to MA and NCI SBIR Contract HHSN261200900061C to MyeloRx LLC.
PY - 2012/3
Y1 - 2012/3
N2 - Triptolide, isolated from the herb Tripterygium wilfordii, has been shown to potently induce apoptosis in various malignant cells by inhibiting RNA synthesis and nuclear factor-κB activity. Previously, we showed that triptolide promotes apoptosis in acute myeloid leukemia (AML) cells via the mitochondria-mediated pathway, in part, by decreasing levels of the anti-apoptotic proteins XIAP and Mcl-1. MRx102 is a triptolide derivative, currently in preclinical development. Here we show that MRx102 potently promoted apoptosis in AML cell lines, with EC 50 values of 14.5±0.6 nM and 37.0±0.9 nM at 48 h for OCI-AML3 and MV4-11 cells, respectively. MRx102, at low nanomolar concentrations, also induced apoptosis in bulk, CD34 + progenitor, and more importantly, CD34 +CD38 - stem/progenitor cells from AML patients, even when they were protected by coculture with bone marrow derived mesenchymal stromal cells. MRx102 decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in OCI-AML3 cells. In vivo, MRx102 greatly decreased leukemia burden and increased survival time in non-obese diabetic/severe combined immunodeficiency mice harboring Ba/F3-ITD cells. Collectively, we demonstrated that MRx102 has potent antileukemic activity both in vitro and in vivo, has the potential to eliminate AML stem/progenitor cells and overcome microenvironmental protection of leukemic cells, and warrants clinical investigation.
AB - Triptolide, isolated from the herb Tripterygium wilfordii, has been shown to potently induce apoptosis in various malignant cells by inhibiting RNA synthesis and nuclear factor-κB activity. Previously, we showed that triptolide promotes apoptosis in acute myeloid leukemia (AML) cells via the mitochondria-mediated pathway, in part, by decreasing levels of the anti-apoptotic proteins XIAP and Mcl-1. MRx102 is a triptolide derivative, currently in preclinical development. Here we show that MRx102 potently promoted apoptosis in AML cell lines, with EC 50 values of 14.5±0.6 nM and 37.0±0.9 nM at 48 h for OCI-AML3 and MV4-11 cells, respectively. MRx102, at low nanomolar concentrations, also induced apoptosis in bulk, CD34 + progenitor, and more importantly, CD34 +CD38 - stem/progenitor cells from AML patients, even when they were protected by coculture with bone marrow derived mesenchymal stromal cells. MRx102 decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in OCI-AML3 cells. In vivo, MRx102 greatly decreased leukemia burden and increased survival time in non-obese diabetic/severe combined immunodeficiency mice harboring Ba/F3-ITD cells. Collectively, we demonstrated that MRx102 has potent antileukemic activity both in vitro and in vivo, has the potential to eliminate AML stem/progenitor cells and overcome microenvironmental protection of leukemic cells, and warrants clinical investigation.
KW - AML and AML stem cells
KW - MRx102
KW - Mcl-1
KW - XIAP
KW - microenvironment
KW - triptolide
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U2 - 10.1038/leu.2011.246
DO - 10.1038/leu.2011.246
M3 - Article
C2 - 21904380
AN - SCOPUS:84857995858
SN - 0887-6924
VL - 26
SP - 443
EP - 450
JO - Leukemia
JF - Leukemia
IS - 3
ER -