PV-0539 Antidiabetic biguanides radiosensitize hypoxic cancer cells through a decrease in oxygen consumption

Recent findings indicate that (a) mitochondria in proliferating cancer cells are functional, (b) cancer cells use more oxygen than normal cells for oxidative phosphorylation, and (c) cancer cells critically rely on cytosolic NADH transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. In a spontaneous lung cancer model, tumor growth was reduced by 50% in heterozygous oxoglutarate carrier (OGC) knock-out mice compared with wild-type counterparts. To determine the mechanism through which OGC promotes tumor growth, the effects of the OGC inhibitor N-phenylmaleimide (NPM) on mitochondrial activity, oxygen consumption, and ATP production were evaluated in melanoma cell lines. NPM suppressed oxygen consumption and decreased ATP production in melanoma cells in a dose-dependent manner. NPM also reduced the proliferation of melanoma cells. To test the effects of NPM on tumor growth and metastasis in vivo, NPM was administered in a human melanoma xenograft model. NPM reduced tumor growth by approximately 50% and reduced melanoma invasion by 70% at a dose of 20 mg/kg. Therefore, blocking OGC activity may be a useful approach for cancer therapy.

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Nitrated Hsp90 Regulates Mitochondrial Membrane Potential and Oxygen Consumption in Cancer Cells

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.10.110 ◽

2012 ◽

Vol 53 ◽

pp. S42-S43

Author(s):

Sarah B. Gitto ◽

Alvaro G. Estévez ◽

María C. Franco

Keyword(s):

Oxygen Consumption ◽

Membrane Potential ◽

Cancer Cells ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane

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Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone

Scientific Reports ◽

10.1038/s41598-020-74808-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Gang Cheng ◽

Micael Hardy ◽

Paytsar Topchyan ◽

Ryan Zander ◽

Peter Volberding ◽

...

Keyword(s):

Oxygen Consumption ◽

Cancer Cells ◽

Complex I ◽

Complex Iii ◽

Antiproliferative Effect ◽

Mitochondrial Complex ◽

Mitochondrial Target ◽

Potent Inhibition ◽

Alkyl Side Chains ◽

First Time

Abstract The FDA-approved prophylactic antimalarial drug atovaquone (ATO) recently was repurposed as an antitumor drug. Studies show that ATO exerts a profound antiproliferative effect in several cancer cells, including breast, ovarian, and glioma. Analogous to the mechanism of action proposed in parasites, ATO inhibits mitochondrial complex III and cell respiration. To enhance the chemotherapeutic efficacy and oxidative phosphorylation inhibition, we developed a mitochondria-targeted triphenylphosphonium-conjugated ATO with varying alkyl side chains (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO). Results show, for the first time, that triphenylphosphonium-conjugated ATO potently enhanced the antiproliferative effect of ATO in cancer cells and, depending upon the alkyl chain length, the molecular target of inhibition changes from mitochondrial complex III to complex I. Mito4-ATO and Mito10-ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito12-ATO and Mito16-ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.

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Overcoming radiation resistance by iron-platinum metal alloy nanoparticles in human copper transport 1-overexpressing cancer cells via mitochondrial targeting

10.21203/rs.3.rs-63975/v1 ◽

2020 ◽

Author(s):

Tsung-Lin Tsai ◽

Yu-Hsuan Lai ◽

Helen H. W. Chen ◽

Wu-Chou Su

Keyword(s):

Reactive Oxygen Species ◽

Oxygen Consumption ◽

Cancer Cells ◽

Radiation Resistance ◽

Oxygen Consumption Rate ◽

Consumption Rate ◽

Reactive Oxygen ◽

Emission Spectrometry ◽

Oxygen Species ◽

Iron Platinum

Abstract Background Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione (GSH) is known to associate with radiation resistance. We used GSH overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells.Methods Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation (IR) were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahoarse XF24 cell energy metabolism analyzer.Results These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased reactive oxygen species (ROS) and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria is the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors.Conclusion These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.

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Dual-emissive, oxygen-sensing boron nanoparticles quantify oxygen consumption rate in breast cancer cells

Journal of Biomedical Optics ◽

10.1117/1.jbo.25.11.116504 ◽

2020 ◽

Vol 25 (11) ◽

Author(s):

Ashlyn G. Rickard ◽

Meng Zhuang ◽

Christopher A. DeRosa ◽

Xiaojie Zhang ◽

Mark W. Dewhirst ◽

...

Keyword(s):

Breast Cancer ◽

Oxygen Consumption ◽

Cancer Cells ◽

Oxygen Consumption Rate ◽

Breast Cancer Cells ◽

Consumption Rate ◽

Oxygen Sensing

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Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Molecular Biology of the Cell ◽

10.1091/mbc.e18-09-0606 ◽

2019 ◽

Vol 30 (5) ◽

pp. 542-553 ◽

Cited By ~ 3

Author(s):

Dong Jun Kim ◽

Mai-Tram Vo ◽

Seong Hee Choi ◽

Ji-Heon Lee ◽

So Yeon Jeong ◽

...

Keyword(s):

Oxygen Consumption ◽

Glucose Metabolism ◽

Cancer Cells ◽

Oxygen Consumption Rate ◽

Consumption Rate ◽

Ectopic Expression ◽

Mrna Degradation ◽

Negative Regulator ◽

Extracellular Acidification ◽

Hexokinase 2

Hexokinase 2 (HK2) catalyzes the first step of glycolysis and is up-regulated in cancer cells. The mechanism has not been fully elucidated. Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that inhibits the expression of ARE-containing genes by enhancing mRNA degradation. TTP expression is down-regulated in cancer cells. We demonstrated that TTP is critical for down-regulation of HK2 expression in cancer cells. HK2 mRNA contains an ARE within its 3′-UTR. TTP binds to HK2 3′-UTR and enhances degradation of HK2 mRNA. TTP overexpression decreased HK2 expression and suppressed the glycolytic capacity of cancer cells, measured as glucose uptake and production of glucose-6-phosphate, pyruvate, and lactate. TTP overexpression reduced both the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cancer cells. Ectopic expression of HK2 in cancer cells attenuated the reduction in glycolytic capacity, ECAR, and OCR from TTP. Taken together, these findings suggest that TTP acts as a negative regulator of HK2 expression and glucose metabolism in cancer cells.

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