The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells

Nagai, Masazumi; Vo, Nha Huu; Ogawa, Luisa Shin; Chimmanamada, Dinesh; Inoue, Takayo; Chu, John Man Tak; Beaudette-Zlatanova, Britte C.; Lu, Rongzhen; Blackman, Ronald K.; Barsoum, James; Koya, Keizo; Wada, Yumiko

doi:10.1016/j.freeradbiomed.2012.03.017

Cited by 184 publications

(228 citation statements)

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“…Copper chelating agents are currently the standard treatment to ameliorate copper overloading of affected tissues in Wilson’s disease [11], whereas early treatment of Menkes disease with copper has shown some promise in newborns having mutations that do not completely abrogate ATP7A [65]. Recent work in model systems has also demonstrated that host cell copper metabolism influences RNA virus replication [66], and leveraging copper’s cytotoxic properties is also being explored for cancer therapy, and may be effective in targeted killing of tumor cells [67-72]. …”

Section: Resultsmentioning

confidence: 99%

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Schlecht

Suresh

et al. 2014

BMC Genomics

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BackgroundCopper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health.ResultsWe found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu’s positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson’s disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin.ConclusionsA functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations.

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Section: Resultsmentioning

confidence: 99%

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Schlecht

Suresh

et al. 2014

BMC Genomics

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“…The encouraging results of a phase II clinical trial of elesclomol in combination with paclitaxel (O'Day et al 2009) were not confirmed in a subsequent phase III trial (O'Day et al 2013). However, it is possible that a population of patients with normal serum lactate dehydrogenase (LDH) levels may respond well to this therapy, whereas high LDH levels may predict a negative clinical effect (Nagai et al 2012;O'Day et al 2013), reflecting the importance of tumor mitochondrial activity.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, normal cells are less sensitive to ROS generation because their ROS content is lower and their antioxidative metabolism is more efficient. The primary mechanism of action of the drug elesclomol [N-malonyl-bis (N 0 -methyl-N 0 -thiobenzoylhydrazide)] is the generation of ROS leading to oxidative stress which induces growth arrest and apoptosis in cancer, but not normal, cells (Kirshner et al 2000;Qu et al 2009;Nagai et al 2012). In preclinical studies, elesclomol sensitized cancer cells to other chemotherapeutic agents (Qu et al 2009;Blackman et al 2012) and, when combined with paclitaxel in a phase II clinical trial, was shown to prolong progressionfree survival in patients with metastatic melanoma (O'Day et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

Rae

Mairs

2016

International Journal of Radiation Biology

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Purpose: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. Although ionizing radiation is used to treat localized and metastatic prostate cancer, the most efficient use of radiotherapy is yet to be defined. Our purpose was to determine in vitro the potential benefit to be gained by combining radiation treatment with cytotoxic drugs. Materials and methods: Inhibitors of DNA repair and heat shock protein 90 and an inducer of oxidative stress were evaluated in combination with X-radiation for their capacity to reduce clonogenic survival and delay the growth of multicellular tumor spheroids. Results: Inhibitors of the PARP DNA repair pathway, olaparib and rucaparib, and the HSP90 inhibitor 17-DMAG, enhanced the clonogenic cell kill and spheroid growth delay induced by X-radiation. However, the oxidative stress-inducing drug elesclomol failed to potentiate the effects of X-radiation. PARP inhibitors arrested cells in the G 2 /M phase when administered as single agents or in combination with radiation, whereas elesclomol and 17-DMAG did not affect radiation-induced cell cycle modulation. Conclusion: These results indicate that radiotherapy of prostate cancer may be optimized by combination with inhibitors of PARP or HSP90, but not elesclomol. ARTICLE HISTORY

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“…S7A) in combination with AC220 and thus was chosen for further study. Elesclomol, which has been evaluated in clinical trials for melanoma, has been shown to selectively transport copper into the mitochondria, to disrupt multiple components of the electron transport chain, and to promote overproduction of mitochondrial ROS (26)(27)(28). In combination with AC220, elesclomol caused synergistic cell killing in both Molm13 cells and MV4-11 cells (Fig.…”

Section: Glutathione Metabolism Is Impaired On Flt3 Inhibition and Fumentioning

confidence: 98%

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 oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells

Cited by 184 publications

References 28 publications

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

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

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