Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

Wondrak, Georg T.

doi:10.1089/ars.2009.2541

Cited by 410 publications

(354 citation statements)

References 382 publications

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“…Indeed, there is also evidence that oncogenes actively up-regulate antioxidant mechanisms to avoid this fate (34). There has recently been extensive focus on exploring ways to exploit the altered redox state of tumor cells through the use of pro-oxidant therapies, thus far with limited success, at least as monotherapy (35)(36)(37). Mitochondria are the major source of ROS in most cells and are highly dependent on mitochondrial antioxidant defenses, such as glutathione peroxidase (about one third of glutathione peroxidase is mitochondrial) to avoid their deleterious effects (38).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Therefore, it is still under debate whether ROS decrease or increase may be more beneficial for the treatment of cancer. Cancer cells may either be affected by the accumulation of ROS above a cytotoxic threshold, or by the inhibition of ROS below a concentration, which is essential for signaling processes (10). Thereby, we assume that the upregulation of ROS may not be the preferred approach, as it may severely affect normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is the need to develop minimally toxic substances to treat patients with highgrade-non-Hodgkin lymphoma efficiently. A novel class of promising chemotherapeutics is the group of reactive oxygen species (ROS)-modulating substances (10). The analysis of ROS and their involvement in the initiation and maintenance of malignancies is an emerging topic in cancer research (11,12).…”

Section: Introductionmentioning

confidence: 99%

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

Klingenberg¹,

Becker²,

Eberth³

et al. 2014

Molecular Cancer Therapeutics

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Burkitt lymphoma is a rare malignancy arising from B cells. Current chemotherapeutic regimens achieve excellent overall survival rates in children, but less impressive rates in adults. There are cases with poor outcome caused by toxic effects of the therapy, tumor lysis syndrome, or metastatic spread of lymphomas to the central nervous system. Modulators of reactive oxygen species are currently discussed as potential drugs for the treatment of cancer. The NADPH oxidase 4 inhibitor imipramine-blue might satisfy the aforementioned requirements, and was studied here. We used MTT assay, crystal violet assay, and thymidine 3H-incorporation assay to analyze the effects of imipramine-blue on Burkitt lymphoma (BL2, BL2B95, BL30B95, BL41B95), neuroblastoma (KELLY, SH-SY5Y, SMS-KAN), cervix carcinoma (HeLa), breast cancer (MDA-MB231), angiosarcoma (AS-M), human embryonic kidney (HEK293WT), and nonmalignant (FLP1) cell lines. The effects of imipramine-blue on BL2B95 cells in vivo were investigated in xenografts on the chick chorioallantoic membrane (CAM). We report that imipramine-blue is a potent growth inhibitor for several cancer cell lines in vitro with IC 50 values comparable to those of doxorubicin (0.16-7.7 mmol/L). Tumor size of BL2B95 cells inoculated in the CAM was reduced significantly (P < 0.05) after treatment with 10 mmol/L imipramine-blue. Lymphogenic dissemination of BL2B95 and the formation of blood and lymphatic vessels in experimental tumors were not affected. We show that imipramine-blue can be used to decrease the viability of cancer cell lines in vitro and in vivo. Imipramine-blue reduces the size of experimental Burkitt lymphoma significantly but does not affect the dissemination of BL2B95 cells, angiogenesis, and lymphangiogenesis.

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“…Importantly, this dependency might not be shared by many nontransformed cells, whose lower basal ROS levels and/or elevated antioxidant capacity could provide resistance to treatments that impair ROS metabolism. 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).…”

mentioning

confidence: 94%

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

Adams

Dai

Pellegrino

et al. 2012

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

201

215

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Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine's induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.

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Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

Cited by 410 publications

References 382 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

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

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

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