Synergistic Anti-Cancer Effect of Phenformin and Oxamate

Miskimins, W. Keith; Ahn, Hyun Joo; Kim, Ji Yeon; Sun, Ruihong; Jung, Yuh‐Seog; Choi, Joon Young

doi:10.1371/journal.pone.0085576

Cited by 113 publications

(120 citation statements)

References 46 publications

(70 reference statements)

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“…Oxamate used in combination with phenformin, one of the anti-diabetic drugs known to reduce cancer risk, was shown to have a synergistic anti-cancer effect in syngenic mouse model. In this case, the LDH-5 inhibitor was demonstrated as a more effective factor than LDHA knockdown [87]. However, none of these inhibitors has thus far been shown in clinical trials.…”

Section: Synthetic Ldh-5 Inhibitors and Their Therapeutic Potentialmentioning

confidence: 89%

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

2015

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Section: Synthetic Ldh-5 Inhibitors and Their Therapeutic Potentialmentioning

confidence: 89%

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

2015

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“…However, if increased mitochondrial ROS could be achieved using alternative means, it could be quite effective in enhancing AML cell killing. To explore this therapeutic strategy, we tested the effects of several drugs known or suspected to cause mitochondrial oxidative stress in leukemia cells, including phenformin and elesclomol (electron transport chain inhibitors) (22,23), tigecycline (inhibitor of mitochondrial translation) (24), and valproic acid (shown to impair ATM levels and induce ROS) (25) for their ability to augment mitochondrial ROS production when combined with FLT3 inhibitor AC220 in Molm13 cells. Elesclomol at nanomolar concentrations was shown to be as effective as ATM or G6PD inhibitors (KU5593 or DHEA) at inducing mitochondrial ROS (Fig.…”

Section: Glutathione Metabolism Is Impaired On Flt3 Inhibition and Fumentioning

confidence: 99%

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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“…The organic cation transporter is responsible for Met uptake into tumor cells, while more lipophilic Met analogs (e.g., phenformin) are taken up into cells via alternate mechanism(s) (11). Phenformin is more potent than Met in inhibiting pancreatic tumor cell proliferation (12). However, phenformin was taken off the market in the U.S. because of increased incidence of acidosis during anti-diabetic therapy (13).…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells

et al. 2016

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Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively-charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogs (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analog Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in non-transformed control cells. Moreover, Mito-Met10 potently triggered G1 cell cycle phase arrest in PDAC cells, enhanced their radiosensitivity and more potently abrogated PDAC growth in preclinical mouse models, compared to Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including in aggressive cancers like PDAC in great need of more effective therapeutic options.

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Synergistic Anti-Cancer Effect of Phenformin and Oxamate

Cited by 113 publications

References 46 publications

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

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

Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells

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