Elesclomol induces cancer cell apoptosis through oxidative stress

Kirshner, Jessica R.; He, Suqin; Balasubramanyam, Vishwasenani; Kepros, Jane; Yang, Chan-Shan; Zhang, Mei; Du, Zhenjian; Barsoum, James; Bertin, John

doi:10.1158/1535-7163.mct-08-0298

Cited by 254 publications

(232 citation statements)

References 35 publications

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“…On the basis of the biochemical differences in cancer cells and normal cells, modulation of oxidative stress has recently been re-emerged as a therapeutic strategy to selectively target the destruction of cancer cells. Great efforts have been made for developing selective anticancer therapeutic agents that increase the level of ROS or alternatively suppress the antioxidant systems 1,12,16,33,[39][40][41] . In this regard, we rationally designed a hybrid anticancer drug QCA to exploit oxidation therapy, which can not only increase the level of ROS but also weaken antioxidant systems simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

et al. 2015

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Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H 2 O 2 and are also susceptible to further ROS insults. Cancer cells adapt to oxidative stress by upregulating antioxidant systems such as glutathione to counteract the damaging effects of ROS. Therefore, the elevation of oxidative stress preferentially in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. Here we report a dual stimuli-responsive hybrid anticancer drug QCA, which can be activated by H 2 O 2 and acidic pH to release glutathione-scavenging quinone methide and ROS-generating cinnamaldehyde, respectively, in cancer cells. Quinone methide and cinnamaldehyde act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. We therefore anticipate that QCA has promising potential as an anticancer therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

et al. 2015

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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: 97%

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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“…Many developmental redox therapeutics have shown a potentiating effect on pharmacodynamic activity of other anticancer agents and radiation, but offer only modest or no chemotherapeutic benefit if used as single agents (9,29,193). Therefore, many ongoing clinical studies test activity of these agents as combinatorial drugs, consistent with the mechanism of action that involves induction of deviations from redox homeostasis that preferentially sensitize cancer cells to the cytotoxic effects of chemotherapeutic agents (9,29,232,246,288).…”

Section: Redox Chemotherapeuticsmentioning

confidence: 99%