Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (Anticancer effects of 3-bromopyruvate through antagonizing Warburg effect)

Sayed, Salah Mohamed El; Mahmoud, Ahmed A.; Sawy, Samer Ahmed El; E, Abdelaal; Fouad, Amira Murad; Yousif, Reda Salah; Hashim, Marwa S.; Hemdan, Shima Badawy; Kadry, Zainab Mahmoud; Abdelmoaty, Mohamed; Gabr, Adel; Omran, Faten M.; Nabo, Manal Mohamed Helmy; Ahmed, Nagwa S.

doi:10.1016/j.mehy.2013.08.024

Cited by 53 publications

(58 citation statements)

References 37 publications

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“…[42,[51][52][53] In accord with published results treatment of both MCF-7 and MDA-MB-231 cells with the glycolytic inhibitors 3BP and 2DG increased ROS levels in the two cell lines. [33,54,55] Combination of either 3BP or 2DG with the CYP2E1 inhibitor CMZ reduced dramatically the oxygen radicals' levels in the MCF-7 but not in the MDA-MB-231 cells [ Figure 2] implying that the dissimilar genetic background in the two cell lines (wild type ER and p53 in MCF-7 and defective ER and mutated p53 in MDA-MB-231 cells) determines the differential response of these cells to the glycolytic and CYP2E1 inhibitors. [56] The observation that CMZ decreased ROS generation stimulated by 3BP and 2DG treatment in MCF-7 cells prompted our interest to explore the possibility that CYP2E1 is involved in the process of energy metabolism in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…[31] On the other hand, experimental evidence supports the view that increased glycolytic conversion to pyruvate leads to ROS generation [32] suggesting the existence of an interrelation between ROS generation with glycolysis and vice versa. [9,33] Taken together, the above mentioned observations allow the hypothesis that overexpression of CYP2E1 and the resultant elevated ROS production might regulate cellular energy metabolism in cancer cells pointing out CYP2E1 as a potential cancer biomarker. The understanding of the interplay between CYP2E1 --ROS generation --cellular energy metabolism can provide important conclusions towards establishing novel breast cancer biomarkers and overcoming drug resistance.…”

Section: Introductionmentioning

confidence: 86%

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Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Singh

Rajendran

Kuroda

et al. 2016

JCMT

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Aim:The aim of the study is to investigate the impact of the cytochrome P450 2E1, which is the most efficient CYP450 family member in generating reactive oxygen species (ROS), on cellular energy metabolism of breast cancer cells and therefore the effects of CYP2E1 on breast carcinogenesis. Methods: The estrogen receptor positive MCF-7 and the triple negative MDA-MB-231 breast cancer cells were used as experimental system to estimate ROS generation in these cells overexpressing CYP2E1 and treated with the glycolytic inhibitors 3-bromopyruvate or 2-deoxyglucose in the presence or absence of the CYP2E1 inhibitor chlormethiazole. Adenosine triphosphate (ATP) assay was used to measure ATP production and lactate assay to quantify the efflux of lactic acid in breast cancer cells treated with the CYP2E1 inhibitor chlormethiazole, the mitochondrial membrane potential and cell viability assays were employed to assess the pathway of cellular energy production and cellular death respectively after treatment of MCF-7 and MDA-MB-231 with the CYP2E1 activator acetaminophen or the CYP2E1 inhibitor chlormethiazole. Results:The results indicated increased ROS generation in breast cancer cells overexpressing CYP2E1. ROS generation was differentially regulated in breast cancer cells upon treatment with the CYP2E1 inhibitor chlormethiazole. Chlormethiazole treated MCF-7 cells exhibited reduced lactate efflux implying that CYP2E1 directly or indirectly regulates the glycolytic rate in these cells. Furthermore the mitochondrial membrane potential of both MCF-7 and MDA-MB-231 cells was differentially affected by the CYP2E1 activator acetaminophen versus the CYP2E1 inhibitor chlormethiazole providing additional support for the involvement of CYP2E1 in energy metabolic pathways in breast cancer. Conclusion: Results presented in this study provide evidence to suggest that CYP2E1 regulates cellular energy metabolism of breast cancer cells in a manner dependent on cell type and potentially on the clinical staging of the disease therefore CYP2E1 is a possible breast cancer biomarker.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Singh

Rajendran

Kuroda

et al. 2016

JCMT

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“…In highly proliferative cells, aberrant metabolism, and protein expression leads to increased rates of ROS production (El Sayed et al, 2013). Cancer cells attempt to counteract the accumulation of ROS by increasing production of NADPH and glutathione, the most abundant antioxidant (Estrela et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

et al. 2015

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NAD 1 kinase (NADK) is the only known cytosolic enzyme that converts NAD 1 to NADP 1 , which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further.

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“…Mitochondrial membrane potential loss and the consequent production of reactive oxygen species (ROS) are the common landmark events of early apoptosis (27). ROS interact with mitochondrial antioxidants and induce apoptosis by releasing cytochrome c from the mitochondria.…”

Section: Shk Damages the Mitochondrial Membrane Potential And Inhibitmentioning

confidence: 99%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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Abstract. Shikonin (SHK) is a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, that has been reported to suppress the growth of a number of cancer cell types. Adriamycin (AD) is typically used as an effective anticancer agent; however, it has the propensity to induce drug resistance. The aim of the present study was to investigate the effects of SHK alone and in combination with AD on lung adenocarcinoma cells and the underlying molecular mechanisms of their effects. Colony formation, MTT and propidium iodide staining assays demonstrated that the co-treatment of A549 cells with SHK and AD significantly decreased cell viability and potently induced apoptosis. The mitochondrial membrane potential was assessed using 5,5', 6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide staining and fluorescence microscopy. Cells co-treated with SHK and AD exhibited marked mitochondrial membrane damage. In addition, co-treatment with SHK and AD significantly reduced ATP levels in A549 cells compared with the control. Western blot analysis revealed that SHK enhanced the antitumor effects of AD by inhibiting the expression of ATP-binding cassette transporters. These results suggest that the inhibition of glycolysis could be an effective approach for lung cancer treatment. Therefore, SHK has the potential to be used as an anticancer agent in the treatment of lung adenocarcinoma, and thus warrants further investigation and development.

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Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (Anticancer effects of 3-bromopyruvate through antagonizing Warburg effect)

Cited by 53 publications

References 37 publications

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

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