Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer

Sun, Li; Yin, Yijun; Clark, Leslie H.; Sun, Wenchuan; Sullivan, Stephanie A.; Tran, Arthur Quan; Han, Jianjun; Zhang, Lu; Guo, Hui; Esther, Madugu,; Pan, Tommy; Jackson, Amanda; Kilgore, Joshua; Jones, Hannah M.; Gilliam, Timothy P.; Zhou, Chunxiao; Bae‐Jump, Victoria L.

doi:10.18632/oncotarget.18854

Cited by 37 publications

(24 citation statements)

References 45 publications

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“…A previous study showed that 2-dG impacted the cell viability of lymphoma cells as a single agent and reduced cell numbers synergistically with PI3K inhibitors and c-MYC antagonists [ 34 ]. Also, inhibition of glycolysis by 2-dG in ovarian cancer cell lines reduced cell proliferation [ 35 ]. Similarly, 2-dG as a single agent was used to selectively kill acute lymphoblastic leukemia cells [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

et al. 2018

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Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.

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Section: Discussionmentioning

confidence: 99%

Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

et al. 2018

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“…Moreover, due to patients' individualities and tumors heterogeneity, variable response rates are often observed making the identification of more effective drugs very urgent [272,273]. In this regard, the concomitant inhibition of antioxidant circuits and metabolic pathways that support the redox balance of malignant cells, delineates a promising anti-cancer strategy [274][275][276][277][278][279][280][281][282][283]. It is known that most of the metabolic changes promoting cancer cells proliferation and tumor growth induce also an increased ROS generation, counterbalanced by an antioxidant response that prevents cell death [234,284,285].…”

Section: Strategies To Negatively Modulate Nrf2 Signaling/pathwaymentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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“…These types of alterations in mitochondrial function specifically in cancer cells have raised prospects for therapeutic targeting of mitochondria in cancer cells. Notably, metabolic profiles defining OXPHOS vs glycolytic status for aGCT cells, as well as EOCs, have yet to be well- reported [ 14 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5

et al. 2018

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BackgroundCellular metabolic changes that accompany malignant transformation have been heralded as hallmark features of cancer. However, metabolic signatures between neoplasms can be unique, allowing for distinctions in malignancy, invasion and chemoresistance between cancer types and subtypes. Mitochondria are central metabolic mediators, as cellular bioenergetics veers from oxidative phosphorylation to glycolysis. Herein, we evaluate the role of mitochondria in maintenance of cellular metabolism, proliferation, and survival in the adult granulosa tumor cell line, KGN, as well as three epithelial ovarian cancer cell lines to determine distinctions in specific features.ResultsNotably, KGN cells were susceptible to TRAIL- and cisplatin-induced death following pretreatment with the metabolic inhibitor FCCP, but not oligomycin A. Collapse of mitochondrial membrane potential was found concomitant with cell death via apoptosis, independent from extrinsic canonical apoptotic routes. Rather, treatment with FCCP resulted in elevated cytochrome c release from mitochondria and decreased responsiveness to BIRC5. Following knockdown of BIRC5, mitochondrial membrane depolarization further sensitized KGN cells to induction of apoptosis via TRAIL.ConclusionsThese results indicate an essential role, distinct from metabolism, for mitochondrial membrane potential in KGN cells to sense and respond to external mediators of apoptotic induction.Electronic supplementary materialThe online version of this article (10.1186/s13048-018-0463-3) contains supplementary material, which is available to authorized users.

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Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer

Cited by 37 publications

References 45 publications

Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells

Potential Applications of NRF2 Modulators in Cancer Therapy

Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5

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