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Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells.

ABSTRACT: Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption. The in vivo experiments in nude mice also showed that DCA and Met synergistically suppressed the growth of xenograft ovarian tumors. These results may pave a way for developing novel strategies for the treatment of ovarian cancer based on the combined use of DCA and Met.

SUBMITTER: Li B

PROVIDER: S-EPMC5312324 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells.

Li Bo B Li Xinzhe X Ni Zhenhong Z Zhang Yan Y Zeng Yijun Y Yan Xiaohuan X Huang Yan Y He Jintao J Lyu Xilin X Wu Yaran Y Wang Yuting Y Zheng Yingru Y He Fengtian F

Oncotarget 20160901 37

Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for ...[more]

PMID: 27449090

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Project description:BackgroundLung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPAR?), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPAR? ligand, AVE8134, on LC growth and progression remain unclear.MethodsA subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~?1?×?106 cells) into their shaved left flank. These mice were treated with three different PPAR? ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth.ResultsThe pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPAR? ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPAR? ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro.ConclusionIn this study, we found that the degrees of inhibition on LC growth and metastasis by PPAR? ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPAR? ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.

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Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells.

Publications

Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells.

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