Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Dunbar, Erin; Coats, Bonnie S.; Shroads, Albert L.; Langaee, Taimour; Lew, Alicia; Forder, John R.; Shuster, Jonathan J.; Wagner, David; Stacpoole, Peter W.

doi:10.1007/s10637-013-0047-4

Cited by 175 publications

(138 citation statements)

References 51 publications

(77 reference statements)

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“…DCA and PENAO are both compounds currently in clinical trials in the treatment of cancer that target different aspects of the cancer metabolic phenotype. [13][14][15]32 Here we demonstrate that PENAO, a novel anti-mitochondrial agent, is effective at low micromolar concentrations against a range of breast cancer cell lines, representing luminal (T-47D and MCF7) and basal (MDA-MB-231 and MDA-MB-468) subtypes of breast cancer, and carcinomas from other tissues (Fig. 1A).…”

Section: Discussionmentioning

confidence: 60%

“…7,8 DCA has been used in the clinic for lactic acidosis disorders for over 3 decades 9,10 and as an anticancer drug, is one of the most promising candidates that targets metabolism, 11,12 with recent reports indicating its safety in cancer patients. [13][14][15] DCA has been demonstrated to halt tumor growth in vivo, 7,[16][17][18] and in glioblastoma patients could normalize the mitochondria, and induce apoptosis in tumors. 15 The induction of apoptosis is said to be via increased production of reactive oxygen species (ROS) due to increased mitochondrial activity, with decreased polarization of the mitochondrial membrane restoring apoptotic processes.…”

Section: Introductionmentioning

confidence: 99%

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Targeting of two aspects of metabolism in breast cancer treatment

Gang

Dilda

Hogg

et al. 2014

Cancer Biology & Therapy

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Keywords: adenine nucleotide transporter, apoptosis, breast cancer, cancer biology, dichloroacetate, metabolism, mitochondria, PENAO, pyruvate dehydrogenase kinase, tumor hypoxiaAbbreviations: ANT, adenine nucleotide translocase; DCA, dichloroacetate; ETC, electron transport chain; MMP, mitochondrial membrane potential; MPTP, mitochondrial permeability transition pore; NAC, N-acetylcysteine; PDK, pyruvate dehydrogenase kinase; PDK2-kd, knock down of PDK2; PENAO, 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid; ROS, reactive oxygen species; siNC, negative control siRNA; siPDK, PDK siRNADeregulated metabolism is gaining recognition as a hallmark of cancer cells, and is being explored for therapeutic potential. The Warburg effect is a metabolic phenotype that occurs in 90% of tumors, where glycolysis is favored despite the presence of oxygen. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the Warburg effect. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel antimitochondrial agent that targets the adenine nucleotide transporter in mitochondria and is currently in clinical trials for solid tumors. We have investigated the targeting of two aspects of metabolism, using DCA to promote mitochondrial activity combined with PENAO to inhibit mitochondrial activity, in breast and other carcinoma cell lines. PENAO was effective at low uM concentrations in luminal (T-47D) and triple negative (MDA-MB-231) breast cancer cells, in normoxia and hypoxia. The cytotoxicity of PENAO was enhanced by DCA by a mechanism involving increased reactive oxygen species in both T-47D and MDA-MB-231 cells, however further investigations found it did not always involve PDK2 inhibition or reduction of the mitochondrial membrane potential, which are the accepted mechanisms for DCA induction of apoptosis. Nevertheless, DCA sensitized all cancer cell lines tested toward apoptosis of PENAO. DCA and PENAO are both currently in clinical trials and targeting cancer metabolism with these drugs may offer options for difficult to treat cancers.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Targeting of two aspects of metabolism in breast cancer treatment

Gang

Dilda

Hogg

et al. 2014

Cancer Biology & Therapy

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“…Because of the fact that dichloroacetate has better in vivo activity than in vitro activity, it also has been suggested that there might be unique metabolic features and special growth pattern for solid tumors that are difficult to recapitulate in vitro and may be critical in determining the efficacy of this class of drugs (46). Dichloroacetate has been used as an orphan drug for various acquired and congenital disorders of mitochondrial metabolism for decades and has recently been proved to be feasible and welltolerated in patients with recurrent malignant gliomas in a recent phase I clinical trial (48). In addition, a recent study has tested the efficacy of dichloroacetate in a small cohort of patients with glioblastoma, suggesting metabolic modulation through PDK inhibition as a novel therapeutic strategy for the treatment of this devastating brain tumor (34).…”

Section: Discussionmentioning

confidence: 99%

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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“…41,45,46 Thus we tested the effects of DCA on ERMS and ARMS cells, either alone or in combination with miR-206 induction. When tested alone, DCA decreased proliferation of both ERMS and ARMS cells, with ARMS cells showing a much greater sensitivity ( Fig.…”

Section: Dca Inhibits Erms and Arms Cell Growth And Enhances The Tumomentioning

confidence: 99%

SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma

et al. 2015

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Rhadomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS cells resemble fetal myoblasts but are unable to complete myogenic differentiation. In previous work we showed that miR-206, which is low in RMS, when induced in RMS cells promotes the resumption of differentiation by modulating more than 700 genes. To better define the pathways involved in the conversion of RMS cells into their differentiated counterpart, we focused on 2 miR-206 effectors emerged from the microarray analysis, SMYD1 and G6PD. SMYD1, one of the most highly upregulated genes, is a H3K4 histone methyltransferase. Here we show that SMYD1 silencing does not interfere with the proliferative block or with the loss anchorage independence imposed by miR-206, but severely impairs differentiation of ERMS, ARMS, and myogenic cells. Thus SMYD1 is essential for the activation of muscle genes. Conversely, among the downregulated genes, we found G6PD, the enzyme catalyzing the rate-limiting step of the pentose phosphate shunt. In this work, we confirmed that G6PD is a direct target of miR-206. Moreover, we showed that G6PD silencing in ERMS cells impairs proliferation and soft agar growth. However, G6PD overexpression does not interfere with the prodifferentiating effect of miR-206, suggesting that G6PD downmodulation contributes to -but is not an absolute requirement for -the tumor suppressive potential of miR-206. Targeting cancer metabolism may enhance differentiation. However, therapeutic inhibition of G6PD is encumbered by side effects. As an alternative, we used DCA in combination with miR-206 to increase the flux of pyruvate into the mitochondrion by reactivating PDH. DCA enhanced the inhibition of RMS cell growth induced by miR-206, and sustained it upon miR-206 de-induction. Altogether these results link miR-206 to epigenetic and metabolic reprogramming, and suggest that it may be worth combining differentiation-inducing with metabolism-directed approaches.

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Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Cited by 175 publications

References 51 publications

Targeting of two aspects of metabolism in breast cancer treatment

Targeting of two aspects of metabolism in breast cancer treatment

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma

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