Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells

Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl A.; Ye, Haobin; Liesveld, Jane L.; O’Dwyer, Kristen M.; Zheng, Lu; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril H.; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

doi:10.1074/jbc.m113.511170

Cited by 173 publications

(200 citation statements)

References 60 publications

(64 reference statements)

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“…CD34 + AML cells were found to have aberrant glutathione metabolism and were sensitive to therapies that further disrupted the glutathione pathway, such as parthenolide and piperlongumine, and it was proposed that AML cells are addicted to glutathione (39). Our results in FLT3-ITD + AML cells support this hypothesis, because FLT3 inhibitors were shown to deplete glutathione, which correlated with increased mitochondrial ROS and the induction of apoptosis.…”

Section: Discussionsupporting

confidence: 78%

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Gregory

D’Alessandro

Alvarez-Calderon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.A cute myeloid leukemia (AML) is a hematological cancer that is characterized by the aberrant growth of myeloid progenitor cells with a block in cellular differentiation. AML is the most common adult acute leukemia and accounts for ∼20% of childhood leukemias. Although frontline treatment of AML with cytotoxic chemotherapy achieves high remission rates, 75-80% of patients will either not respond to or will relapse after initial therapy, and most patients will die of their disease (1, 2). Thus, more effective and less toxic therapies for AML are required. The promise of molecularly targeted cancer therapies has generated much excitement with the remarkable clinical success of the small molecule tyrosine kinase inhibitors (TKIs) targeting the oncogenic kinase BCR-ABL for the treatment of chronic myeloid leukemia (3). However, targeted approaches for the treatment of AML have not yet yielded major successes.In AML, aberrant signal transduction drives the proliferation and survival of leukemic cells. Activated signal transduction occurs through genetic alterations of signaling molecules such as FLT3, KIT, PTPN11, and members of the RAS family (4, 5). Given the successful development and utilization of numerous TKIs, the FLT3 receptor tyrosine kinase has emerged as a promising target for the treatment of AML. Indeed, activating mutations in FLT3 are one of the most frequently observed genetic defects in AML and are comprised predominantly of internal tandem duplication (ITD) mutations in the juxtamembrane domain (6). FLT3-ITD mutations are associated with poor prognosis, including increased relapse rate, decreased disease-free survival, and poor overall survival (5,7,8). The cl...

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Section: Discussionsupporting

confidence: 78%

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Gregory

D’Alessandro

Alvarez-Calderon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Using LC-MS/MS of each fraction, we subsequently identified 312 binding targets of PTL in primary AML cells (supplemental Table 1). Notably, several previously reported binding targets of PTL including IKK␤, GCLC, GPX1, and TXN were all successfully identified through this approach (25)(26)(27), suggesting our method had good specificity and coverage. Subsequently, we employed the Ingenuity Pathway Analysis (IPA) software and identified a list of pathways/biological functions that are significantly represented by this pool of binding targets (supplemental Table 2).…”

Section: Identification Of the Proteomic Interactome Of Ptl In Primarymentioning

confidence: 89%

“…Although previous studies by our group and others have shown that PTL is a strong inhibitor of the NF-B pathway and also a potent inhibitor of glutathione metabolism (22,(25)(26)(27)(28)(29), there have been very few studies that systematically characterize its anti-cancer mechanism at a multi-omic level. In the present study, we investigated the mechanism of PTL by first using a biotinylated analog to identify its proteomic interactome.…”

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confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

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“…Interestingly, this effect was observed in CML CD34 + lin − cells, but not on their normal counterpart. NBM primitive cells showed lower basal levels of ROS than their CML counterpart, this could indicate higher levels of reduced glutathione in normal populations, which would make normal primitive cells resilient to PTL and DMAPT effect as has been observed in CD34+ cells from AML samples,13 and proves a key mechanism to be exploited and further studied. PTL and DMAPT also inhibited phosphorylation and nuclear localization of NF‐κB (p65).…”

Section: Discussionmentioning

confidence: 84%

“…To improve the pharmacological properties of PTL, an orally bioavailable analogue was generated, dimethyl amino parthenolide (DMAPT) that showed similar activity to PTL in AML LSC11; nevertheless, the effect on CML cells, including both primitive primary cells, as well as CML cell lines, is unknown. The mechanism of action of PTL has been reported to rely on a number of pathways, two of which are the inhibition of NF‐κB via the alkylation of critical cysteine residues12 and the induction of ROS by affecting the glutathione system 13…”

Section: Introductionmentioning

confidence: 99%

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

Flores‐Lopez

Moreno‐Lorenzana

Ayala-Sánchez

et al. 2018

J Cellular Molecular Medi

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Tyrosine kinase inhibitors (TKI) have become a first‐line treatment for chronic myeloid leuakemia (CML). TKIs efficiently target bulk CML cells; however, they are unable to eliminate the leukaemic stem cell (LSC) population that causes resistance and relapse in CML patients. In this study, we assessed the effects of parthenolide (PTL) and dimethyl amino parthenolide (DMAPT), two potent inhibitors of LSCs in acute myeloid leukaemia (AML), on CML bulk and CML primitive (CD34+lin−) cells. We found that both agents induced cell death in CML, while having little effect on the equivalent normal hematopoietic cells. PTL and DMAPT caused an increase in reactive oxygen species (ROS) levels and inhibited NF‐κB activation. PTL and DMAPT inhibited cell proliferation and induced cell cycle arrest in G0 and G2 phases. Furthermore, we found cell cycle inhibition to correlate with down‐regulation of cyclin D1 and cyclin A. In summary, our study shows that PTL and DMAPT have a strong inhibitory effect on CML cells. Given that cell cycle arrest was not dependent on ROS induction, we speculate that this effect could be a direct consequence of NF‐κB inhibition and if this mechanism was to be evaded, PTL and DMAPT induced cell death would be potentiated.

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Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells

Cited by 173 publications

References 60 publications

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

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