Heterogeneity of glycolysis in cancers and therapeutic opportunities

Warmoes, Marc O.; Locasale, Jason W.

doi:10.1016/j.bcp.2014.07.019

Cited by 48 publications

(37 citation statements)

References 162 publications

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“…Studies with cells that underwent chemically induced partial or total depletion of mitochondrial function have supported a role for mitochondrial dysfunction in cancer drug resistance. It has been reported that partial or total depletion of mitochondrial function causes cancer cells to become less sensitive to the chemotherapeutic drugs cisplatin and paclitaxel …”

Section: Discussionmentioning

confidence: 99%

Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum‐based adjuvant chemotherapy

et al. 2016

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Volumetric parameters of positron emission tomography–computed tomography using 18F‐fludeoxyglucose (18F‐FDG PET/CT) that comprehensively reflect both metabolic activity and tumor burden are capable of predicting survival in several cancers. The aim of this study was to investigate the predictive performance of metabolic tumor burden measured by 18F‐FDG PET/CT in ovarian cancer patients who received platinum‐based adjuvant chemotherapy after cytoreductive surgery. Included in this study were 37 epithelial ovarian cancer patients. Metabolic tumor burden in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG), clinical stage, histological type, residual tumor after primary cytoreductive surgery, baseline serum carbohydrate antigen 125 (CA125) level, and the maximum standardized uptake value (SUVmax) were determined, and compared for their performance in predicting progression‐free survival (PFS). Metabolic tumor volume correlated with CA125 (r = 0.547, P < 0.001), and TLG correlated with SUVmax and CA125 (SUVmax, r = 0.437, P = 0.007; CA125, r = 0.593, P < 0.001). Kaplan–Meier analysis showed a significant difference in PFS between the groups categorized by TLG (P = 0.043; log–rank test). Univariate analysis indicated that TLG was a statistically significant risk factor for poor PFS. Multivariate analysis adjusted according to the clinicopathological features was carried out for MTV, TLG, SUVmax, tumor size, and CA125. Only TLG showed a significant difference (P = 0.038), and a 3.915‐fold increase in the hazard ratio of PFS. Both MTV and TLG (especially TLG) could serve as potential surrogate biomarkers for recurrence in patients who undergo primary cytoreductive surgery followed by platinum‐based chemotherapy, and could identify patients at high risk of recurrence who need more aggressive treatment.

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Section: Discussionmentioning

confidence: 99%

Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum‐based adjuvant chemotherapy

et al. 2016

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“…This unique metabolic behavior of tumor cells is known as the “Warburg effect” (8–11). In addition to previously reported metabolic states such as the Warburg effect, it is thought that cancer cells may respond differently metabolically to microenvironmental perturbations (12–14). We hypothesized that, after exposure to radiation, detectable and quantifiable changes in metabolism might occur, very quickly, from the physical effects of the radiation itself.…”

Section: Introductionmentioning

confidence: 95%

Radiation Promptly Alters Cancer Live Cell Metabolic Fluxes: An In Vitro Demonstration

Campos¹,

Peeters

Nickel

et al. 2016

Radiation Research

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Quantitative data is presented that shows significant changes in cellular metabolism in a head and neck cancer cell line 30 min after irradiation. A head and neck cancer cell line (UM-SCC-22B) and a comparable normal cell line, normal oral keratinocyte (NOK) were each separately exposed to 10 Gy and treated with a control drug for disrupting metabolism (potassium cyanide; KCN). The metabolic changes were measured live by fluorescence lifetime imaging of the intrinsically fluorescent intermediate metabolite nicotinamide adenosine dinucleotide (NADH) fluorescence; this method is sensitive to the ratio of bound to free NADH. The results indicated a prompt shift in metabolic signature in the cancer cell line, but not in the normal cell line. Control KCN treatment demonstrated expected metabolic fluxes due to mitochondrial disruption. The detected radiation shift in the cancer cells was blunted in the presence of both a radical scavenger and a HIF-1α inhibitor. The HIF-1α abundance as detected by immunohistochemical staining also increased substantially for these cancer cells, but not for the normal cells. This type of live-cell metabolic monitoring could be helpful for future real-time studies and in designing adaptive radiotherapy approaches.

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“…have suggested that cancer cells have a heterogeneous metabolic profile and some cancer cell populations use glycolysis as a main energetic pathway, while others use oxidative phosphorylation. The large heterogeneity in mitochondrial glycolytic enzymes, spliced forms, and posttranslational modifications offer an array of antiglycolytic agents as candidate therapeutics on the basis of the molecular signatures of the patient . Several in vivo imaging strategies are now available to assess changes in flux through glycolysis by using positron emission tomography or advanced technologies exploiting the properties of heavy labeled, hyperpolarized nutrients (e.g., choline, acetate, and glutamine) .…”

Section: Summary and Future Research Directionsmentioning

confidence: 99%

Mitochondrial dynamics regulating chemoresistance in gynecological cancers

Kong

Tsuyoshi

Orisaka

et al. 2015

Annals of the New York Academy of Sciences

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Chemoresistance enables cancer cells to evade apoptotic stimuli and leads to poor clinical prognosis. It arises from dysregulation of signaling factors responsible for inducing cell proliferation and death and for modulating the microenvironment. In gynecologic cancers, p53 is a pivotal determinant of cisplatin sensitivity, while BCL-2 family members are associated with taxane sensitivity. Mitochondria fusion and fission dynamics are required for many mitochondrial functions and are also involved in mitochondria-mediated apoptosis, which is closely associated with chemosensitivity. Mitochondrial dynamics are controlled by a number of intracellular proteins, including fusion (Opa1 and mitofusion 1 and 2) and fission proteins (Drp1 and Fis1), which can be proapoptotic or antiapoptotic, depending on the cell types, status, and stimuli from the microenvironment. This paper describes the role of mitochondrial dynamics in the mechanism of chemoresistance and the evidence supporting a significant contribution of a hyperfusion state to chemoresistance in gynecological cancers. Moreover, we discuss our findings showing that enforced fission induces apoptosis of cancer cells and sensitizes them to chemotherapeutic agents. Understanding the regulation of mitochondrial dynamics in chemoresistance may provide insight into new biomarkers that better predict cancer chemosensitivity and may aid the development of effective therapeutic strategies for clinical management of gynecologic cancers.

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Heterogeneity of glycolysis in cancers and therapeutic opportunities

Cited by 48 publications

References 162 publications

Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum‐based adjuvant chemotherapy

Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum‐based adjuvant chemotherapy

Radiation Promptly Alters Cancer Live Cell Metabolic Fluxes: An In Vitro Demonstration

Mitochondrial dynamics regulating chemoresistance in gynecological cancers

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