Dichloroacetate causes toxic neuropathy in MELAS

Kaufmann, Petra; Engelstad, Kristin; Wei, Ying; Jhung, Sarah; Sano, Mary; Shungu, Dikoma C.; Millar, William S.; Hong, Xiaoni; Gooch, Clifton L.; Mao, Xiangling; Pascual, Juan M.; Hirano, Michio; Stacpoole, Peter W.; DiMauro, Salvatore; Vivo, Darryl C. De

doi:10.1212/01.wnl.0000196641.05913.27

Cited by 322 publications

(251 citation statements)

References 25 publications

Supporting

Mentioning

239

Contrasting

Unclassified

Order By: Relevance

“…It was suggested that DCA could rapidly translate to cancer clinical trials because it has been used to treat lactic acidosis and found to be relatively safe in humans (43,44). However, the doses of DCA required to induce apoptosis in cancer cells are very high and unlikely to be achieved clinically without causing significant side effects (45). When combined with 5-FU, low doses of DCA and 5-FU could significantly induce apoptosis in colon cancer cells.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg À1 day À1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study.…”

Section: Dca: Mechanism Of Action and Clinical Experiencementioning

confidence: 99%

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

2008

View full text Add to dashboard Cite

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

show abstract

“…Therefore, a third trial was organized at Columbia University, which was specific for MELAS [10]. This also was a phase III double-blind, randomized, placebocontrolled trial (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

View full text Add to dashboard Cite

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

show abstract

Dichloroacetate causes toxic neuropathy in MELAS

Cited by 322 publications

References 25 publications

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

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

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Contact Info

Product

Resources

About