Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Allen, Kah Tan; Chin-Sinex, Helen; DeLuca, Thomas H.; Pomerening, Joseph R.; Sherer, Jeremy; Watkins, John B.; Foley, John; Jesseph, Jerry M.; Mendonca, Marc S.

doi:10.1016/j.freeradbiomed.2015.08.006

Cited by 35 publications

(29 citation statements)

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“…In our study, we provided the rst evidence that UCA1 knockdown impeded the viability and glycolysis of NSCLC cells by suppressing PKM2 expression through the mTOR pathway in NSCLC, shedding light on the specic regulatory mechanism of UCA1 in NSCLC. The Warburg effect, characterized by increased glucose consumption and lactate production even in sufficient oxygen state, 30 is considered as a well-recognized hallmark of cancer cells. 31 Accumulating evidence indicates that reprogrammed energy metabolism, including hyperactive aerobic glycolysis, is frequently observed in human cancers, which is accompanied by the facilitated cell proliferation and growth.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of UCA1 inhibits viability and glycolysis by suppressing PKM2 expression through the mTOR pathway in non-small cell lung cancer cells

Wang

2018

RSC Adv.

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Section: Discussionmentioning

confidence: 99%

Knockdown of UCA1 inhibits viability and glycolysis by suppressing PKM2 expression through the mTOR pathway in non-small cell lung cancer cells

Wang

2018

RSC Adv.

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“…In order to verify if the effect exerted by DCA on cancer cell vitality was due to a perturbation of their cell cycle, as reported for glioblastoma, glioma, non-small cell lung cancer and other cancer cell lines (33)(34)(35)(36), TS/A cells were incubated with DCA for 24 h, then stained with PI and analysed by flow cytometry. As shown in the graph ( fig.…”

Section: Dca Metabolic Inhibition Impairs Ts/a Proliferation But Not mentioning

confidence: 99%

In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging

Anemone

Consolino

Conti

et al. 2017

International Journal of Oncology

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Dichloroacetate (DCA) can reverse the glycolytic phenotype that is responsible of increased lactate production and extracellular pH acidification in cancer cells. Magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) pH mapping is a novel non-invasive imaging approach that can measure in vivo extracellular tumour pH. We examined whether MRI-CEST pH mapping can monitor in vivo changes in tumour acidosis for assessing treatment response to DCA. Cell viability and extracellular pH were assessed in TS/A breast cancer cells treated with 1-10 mM DCA for 24 h in normoxia or hypoxia (1% O2) conditions. Extracellular tumour pH values were measured in vivo by MRI-CEST pH mapping of TS/A tumour-bearing mice before, three days and fifteen days after DCA or saline treatment. Reduced extracellular acidification and vitality were observed in DCA-treated TS/A cells. Tumour-bearing mice showed a marked and significant increase of tumour extracellular pH at 3 days post-DCA treatment, reflecting DCA-induced glycolysis inhibition, as confirmed by reduced lactate production. After 15 days of DCA treatment, the onset of resistance to DCA was observed, with recover of tumour extracellular acidification and lactate levels that returned to baseline values. A significant correlation was observed between tumour extracellular pH values and lactate levels (r= -0.97, P<0.05). These results suggest that MRI-CEST pH imaging is a promising tool to monitor the early response and efficacy of cancer metabolic targeting drugs.

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“…Colorectal cancer (CRC) is the fourth leading cause of cancer-related death in China [1] and is the second leading cause of cancer-related mortality in the United States [2], which mainly attributes to metastasis and chemotherapy These authors contributed equally: Yu Liang, Lidan Hou failure due to drug resistance, leading to~50,000 deaths annually [3].…”

Section: Introductionmentioning

confidence: 99%

“…Briefly, mice were subcutaneously implanted with 6 × 10 6 HCT-8/F cells. After the tumor sizes were~50 mm 3 , mice received an intraperitoneal dosage of 5-FU (10 mg/kg) every other day as well as an intratumoral injection of 5 nmol cholesterol-conjugated miR-149-3p mimics or a NC every 3 days for 3 weeks. Later, three mice from each group were fasted overnight and were intravenously injected with 0.15 mCi 18F-FDG.…”

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confidence: 99%

Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway

Hou

et al. 2019

Oncogene

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The development of chemoresistance remains a major challenge that accounts for colorectal cancer (CRC) lethality. Dichloroacetate (DCA) was originally used as a metabolic regulator in the treatment of metabolic diseases; here, DCA was assayed to identify the mechanisms underlying the chemoresistance of CRC. We found that DCA markedly enhanced chemosensitivity of CRC cells to fluorouracil (5-FU), and reduced the colony formation due to high levels of apoptosis. Using the microarray assay, we noted that miR-149-3p was involved in the chemoresistance of CRC, which was modulated by wild-type p53 after DCA treatment. In addition, PDK2 was identified as a direct target of miR-149-3p. Mechanistic analyses showed that overexpression of miR-149-3p enhanced 5-FU-induced apoptosis and reduced glucose metabolism, similar to the effects of PDK2 knockdown. In addition, overexpression of PDK2 partially reversed the inhibitory effect of miR-149-3p on glucose metabolism. Finally, both DCA treatment and miR-149-3p overexpression in 5-FU-resistant CRC cells were found to markedly sensitize the chemotherapeutic effect of 5-FU in vivo, and this effect was also validated in a small retrospective cohort of CRC patients. Taken together, we determined that the p53/miR-149-3p/PDK2 signaling pathway can potentially be targeted with DCA treatment to overcome chemoresistant CRC.

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Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

Cited by 35 publications

References 50 publications

Knockdown of UCA1 inhibits viability and glycolysis by suppressing PKM2 expression through the mTOR pathway in non-small cell lung cancer cells

Knockdown of UCA1 inhibits viability and glycolysis by suppressing PKM2 expression through the mTOR pathway in non-small cell lung cancer cells

In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging

Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway

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