Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use.Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylaminoparthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-B, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.
IntroductionRecent studies have demonstrated that myeloid leukemia and certain forms of lymphoid leukemia arise from malignant stem cells (called leukemia stem cells [LSCs]). [1][2][3] LSCs are typically found in a quiescent state and are thus unlikely to respond to standard chemotherapeutic agents that preferentially eradicate actively cycling cells. [4][5][6][7] Indeed, the persistence of LSCs following chemotherapy may be a major factor contributing to clinical relapse. 8,9 In addition, conventional leukemia therapy is also substantially toxic to normal hematopoietic cells and frequently results in severe myelosuppression. Therefore, given the drugrefractory nature of LSCs, and the importance of normal hematopoiesis, identification of less toxic and more specific forms of therapy are important priorities for the development of better therapeutic regimens.As a foundation for developing more selective leukemia treatments, our previous experiments have investigated basic properties of primitive acute myelogenous leukemia (AML) cells. These studies showed that LSCs from different AML subtypes share characteristics 10 that are unique to AML and thus represent potential therapeutic targets for the selective ablation of LSCs relative to their normal counterparts. 11,12 Specifically, we reported that NF-B, a known regulator of growth and survival, is constitutively active in LSCs but not in normal hematopoietic stem cells (HSCs). 13 Notably, many traditional cancer therapies induce activation of NF-B, a potentially undesirable characteristic likely to facilitate survival of malignant cells. 14,15 Given the abi...
