Dichloroacetate induces autophagy in colorectal cancer cells and tumours

Lin, Gigin; Hill, Deborah K.; Andrejeva, Gabriela; Boult, Jessica K.R.; Troy, Helen; Fong, A-C L F W T; Orton, Matthew; Panek, Rafał; Parkes, Harold G.; Jafar, Maysam; Koh, Dow‐Mu; Robinson, Simon P.; Judson, Ian; Griffiths, John R.; Leach, Martin O.; Eykyn, Thomas R.; Chung, Yuen Li

doi:10.1038/bjc.2014.281

Cited by 75 publications

(62 citation statements)

References 50 publications

(67 reference statements)

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“…It has been reported that dichloroacetate treatment induced ROS production both in vitro and in vivo (44). Recent evidence also indicated that dichloroacetate increases autophagy in association with increased ROS production in colorectal cancer cells (45). Given ROS plays an important role in their individual mode of action of dichloroacetate and radiotherapy, we thus combined dichloroacetate with radiotherapy and demonstrated that the combination treatment not only increased the ROS production but also caused higher level of double-strand breaks than each treatment alone.…”

Section: Discussionmentioning

confidence: 88%

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Shen

Hau

Joshi

et al. 2015

Molecular Cancer Therapeutics

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Because radiotherapy significantly increases median survival in patients with glioblastoma, the modulation of radiation resistance is of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance; thus, the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Metabolically, the elevated glycolysis in glioblastoma cells was observed postradiotherapy together with upregulated hypoxia-inducible factor (HIF)-1a and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, a PDK inhibitor currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of glioblastoma and has the ability to reverse the radiotherapy-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of glioblastoma cells was observed when dichloroacetate was combined with radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized glioblastoma cells to radiotherapy by inducing the cell-cycle arrest at the G 2 -M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in glioblastoma cells together with radiotherapy. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and radiotherapy in clinical trials.

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Section: Discussionmentioning

confidence: 88%

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Shen

Hau

Joshi

et al. 2015

Molecular Cancer Therapeutics

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“…Thus, increased expression of BH3-only proteins upon DCA treatment leads to Bax activation and cytochrome C release, causing the induction of apoptosis in cancer cells. DCA enhances ROS production, resulting in the induction of autophagy via suppression of Akt-mammalian target of rapamycin (mTOR) signaling [87, 88]. In addition to cell death induction, the anticancer effects of DCA also include inhibition of cancer cell proliferation [89].…”

Section: Restoration Of Mitochondrial Function By Dca As a Potential mentioning

confidence: 99%

Restoration of mitochondria function as a target for cancer therapy

Bhat

Kumar

Chaudhary

et al. 2015

Drug Discovery Today

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Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and whether and/or how restoration of mitochondrial function could be exploited for cancer therapeutics.

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“…In brief, autophagy is a cytoprotective mechanism to protect normal cellular survival. When abnormality in the process of autophagy occurs, normal cellular functions become damaged, and the accumulated abnormalities will lead to systematic problems [17]. Abundant evidence shows that autophagy is associated with the genesis and development of cancers, and effective therapeutic strategies could induce or inhibit the process of autophagy in various cancers [18].…”

Section: Introductionmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) Inhibitor S2101 Induces Autophagy via the AKT/mTOR Pathway in SKOV3 Ovarian Cancer Cells

et al. 2016

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BackgroundS2101 is one of the most potent LSD1 inhibitors, which can inhibit ovarian cancer cells viability. This study aimed to detect the mechanism behind the anticancer properties of S2101 in SKOV3 ovarian cells.Material/MethodsCell viability was tested by Cell Counting Kit-8 (CCK-8) assay. Cellular apoptosis and autophagy were evaluated by flow cytometric analysis using Annexin-V/PI staining methods and Green fluorescent protein (GFP)-fused-LC3 (GFP-LC3), respectively. Western blotting was performed for analyzing the Bax, Bcl-2, mTOR, p-mTOR, p62, LC3-I, LC3-II, AKT, and p-AKT protein expression.ResultsOur results show that the proportion of early apoptotic and late apoptotic cells increased significantly for cells treated with S2101 at a concentration of 100 μM for 48 h. Treatment of S2101 in SKOV3 cells resulted in upregulation of Bax and downregulation of Bcl-2 in a time-dependent manner, indicating that S2101 can induce apoptosis in SKOV3. There was a downward trend in the expression of p62 when the SKOV3cells were treated with 100 μm S2101 for 12 h, 24 h and 48 h. The conversion of LC3-I to LC3-II was increased significantly at 24 h and 48 h. Autophagy was induced by S2101 in SKOV3 cells, evidenced by an increase in punctuate localization of GFP-LC3 and a change in expression of autophagy-related proteins.ConclusionsS2101 treatment decreased the levels of phosphorylated AKT and mTOR. S2101 inhibits SKOV3 cells viability and induces apoptosis and autophagy. The AKT/mTOR signaling pathway was found to be affected by S2101.

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Dichloroacetate induces autophagy in colorectal cancer cells and tumours

Cited by 75 publications

References 50 publications

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Restoration of mitochondria function as a target for cancer therapy

Lysine-Specific Demethylase 1 (LSD1) Inhibitor S2101 Induces Autophagy via the AKT/mTOR Pathway in SKOV3 Ovarian Cancer Cells

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