An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells

Abstract

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...

The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia

“…Furthermore, Akti-1/2 activity in this cellular fraction was enhanced by low-dose DNR, in line with earlier studies, suggesting that the mechanism of LSC death involves the combined inhibition of survival pathways and activation of stress pathways. 46 In conclusion, this study shows that AML cells with high-risk cytogenetics display a high level of phospho-Akt Thr308, correlating with a decrease in PP2A activity and a potent effect of the Akt inhibitor, Akti-1/2, on AML cell proliferation, survival and clonogenicity. This suggests that this anti-apoptotic pathway may be a valuable therapeutic target, particularly in high-risk cytogenetic AML.…”

Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I

“…20 In recent years, the anti-cancer properties of various STLs have attracted interest, and extensive research has been carried out to characterize the anti-cancer activity and the potential chemotherapeutic application of STLs. [35][36][37] On the molecular level, the effects of STLs on cell signaling pathways such as nuclear transcription factorkappaB (NF-kB) and mitogen-activated protein kinases have been intensely studied. [38][39][40] Previous work has implicated c-Myb as a potential therapeutic target in several types of human tumors, including colon cancer, breast cancer and leukemia.…”

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

“…In keeping with this hypothesis, various small molecules, including ones with disulfide, α,β-unsaturated carbonyl, sulfonate, or other electrophilic functional groups, have previously been shown to elevate ROS levels and induce cancer cell death (6). A subset of such compounds has also demonstrated a degree of selective toxicity toward cancer cells in in vitro and in vivo models (7)(8)(9)(10)(11)(12).…”