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Acute Leukemias

MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML

Leukemia volume 26, pages 443–450 (2012)Cite this article

Abstract

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 EC50 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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Z Carter, D H Mak, Y Shi, X Ling & M Andreeff

  2. MyeloRx LLC, Vallejo, CA, USA

    J M Fidler

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R Chen & W Plunkett

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  1. B Z Carter
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Correspondence to M Andreeff.

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JMF is an employee of MyeloRx and all the other authors have no conflict of interest.

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Carter, B., Mak, D., Shi, Y. et al. MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML. Leukemia 26, 443–450 (2012). https://doi.org/10.1038/leu.2011.246

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