Dichloroacetate induces apoptosis in endometrial cancer cells

Wong, Jason; Huggins, Gordon S.; Debidda, Marcella; Munshi, Nikhil C.; Vivo, Immaculata De

doi:10.1016/j.ygyno.2008.01.038

Cited by 189 publications

(201 citation statements)

References 39 publications

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“…DCA has been shown to attenuate 5-FU resistance in gastric cancer cells (14). In preclinical studies, different cancer cells showed different responses to DCA-induced apoptosis (32)(33)(34). We next investigated whether DCA would increase the effectiveness of 5-FU against colon cancer cells.…”

Section: Genetic or Pharmacological Inhibition Of Pdk4 Sensitizes Colmentioning

confidence: 99%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGF␤ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGF␤ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGF␤ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGF␤/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.Colorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer mortality in the United States. In addition to surgery, treatment for colorectal cancer patients, especially for patients with advanced disease, primarily relies on chemotherapy and radiation therapy. 5 is one of the most commonly used chemotherapeutic agents for colorectal cancer treatment. It induces cell cycle arrest and apoptosis in cancer cells (1). Although adjuvant 5-FU treatment has a good success rate, the high recurrence is still a major hurdle of treating colorectal cancer because of the resistance to chemotherapeutic drugs. Therefore, it is important to understand the mechanisms of drug resistance and identify new targets to increase the effectiveness of chemotherapy in colorectal cancer. TGF␤ plays an important role in cancer development and progression. Upon ligand binding, TGF␤ type II receptor (RII) recruits and activates TGF␤ type I receptor (RI), which then activates Smad2 and Smad3. Activated Smad2 and Smad3 form complexes with Smad4 and translocate to the nucleus, where they regulate gene expression (2). We and others have demonstrated that TGF␤ suppresses tumorigenicity in a variety of cancers, including colorectal cancer, and that loss of TGF␤ signaling leads to malignancy (3-6). Although many studies have shown that TGF␤ promotes metastasis (7), others have demonstrated that TGF␤ suppresses metastasis (8,9). Recently, studi...

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Section: Genetic or Pharmacological Inhibition Of Pdk4 Sensitizes Colmentioning

confidence: 99%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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“…In contrast, the efficacy of radiotherapy was sensitized by dichloroacetate with 150 mg/kg/d in vivo that gives much lower serum level of dichloroacetate. This finding is consistent with previous reports describing that this anti-metabolic compound has better in vivo efficacy than in vitro activity (37,46,47). The reasons for the limited antitumor effect of dichloroacetate with clinically relevant doses in vitro may lie in the complex cellular physiology and the immense excess of metabolites existing in cell culture media (46).…”

Section: Discussionsupporting

confidence: 92%

“…In the current study, we further analyzed the cell-cycle distribution after dichloroacetate treatment showing that dichloroacetate induced G 2 -M arrest and decreased the cell proportion in S-phase. These findings are consistent with some (35,36), but not all studies (12,37), indicating not all cancer types share the same mechanism of action after dichloroacetate treatment. As cancer cells are most sensitive to radiotherapy in the G 2 -M phase of the cell cycle whereas most resistance in the S-phase (38-40), our results suggest that dichloroacetate treatment can sensitize glioblastoma cells to radiotherapy by altering cell cycle-distribution.…”

Section: Discussionsupporting

confidence: 90%

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Shen

Hau

Joshi

et al. 2015

Molecular Cancer Therapeutics

100

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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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“…Being an orphan drug, DCA is both nonpatentable and readily available, but it is not yet approved for use in cancer therapy (15). There is substantial preclinical evidence from both in vitro and in vivo models that DCA might be useful to treat cancer in humans, and a translation to earlyphase clinical trials would be of interest (16)(17)(18). Funding for such trials would be a challenge because DCA is a generic drug.…”

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confidence: 99%