Quantitative evaluation of dichloroacetic acid kinetics in human—a physiologically based pharmacokinetic modeling investigation

Li, Ting; Schultz, Irv; Keys, Deborah A.; Campbell, Jerry L.; Fisher, Jeffrey W.

doi:10.1016/j.tox.2007.12.010

Cited by 19 publications

(18 citation statements)

References 38 publications

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“…However, mitaplatin, a compound where two DCA molecules were appended to the axial positions of a six-coordinate Pt(IV) centre, showed promising activity [54,55]. Our results demonstrate that DCA inhibits growth of the chemoresistant UMC-11 cell line and sensitises the cells to carboplatin, JM118 and oxoplatin at concentrations that can be achieved in vivo [56]. The mechanism of this selectivity of DCA for specifi c platinum compounds remains to be elucidated.…”

Section: Discussionmentioning

confidence: 78%

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

et al. 2011

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The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.

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Section: Discussionmentioning

confidence: 78%

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

et al. 2011

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“…While it is true that biotransformation to the inactive metabolite, glyoxylate, reduces the bioavailability of parent DCA through first-pass metabolism, at least for the first dose (Li, et al, 2008; Saghir & Schultz, 2002), DCA as a small, water- and lipid-soluble molecule readily crosses membranes and is completely absorbed following oral administration (James, et al, 1998). As discussed in section 2, DCA is known to be a substrate for uptake transporters (Babu, et al, 2011; Jackson & Halestrap, 1996; McCommis & Finck, 2015), however further studies are needed to fully describe the intercellular and intracellular transport of DCA.…”

Section: Biotransformation Of Dca Role Of Gstz1mentioning

confidence: 99%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

110

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…The mechanisms leading to synergy of DCA with some platinum drugs, especially carboplatin, satraplatin, and JM118, are not clear. High doses of DCA (approximately 50 mg/kg) are used clinically to treat metabolic acidosis, and biotransformation of DCA by glutathione S-transferase ζ in the liver is the major elimination pathway in humans 21. DCA was shown to suppress the expression of several cytochrome P450 enzymes and glutathione S-transferase π1, by two- to fivefold in rodents 9.…”

Section: Discussionmentioning

confidence: 99%

In vitro cytotoxicity of combinations of dichloroacetate with anticancer platinum compounds

Hamilton¹

2010

CPAA

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PurposeDichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), and thus promotes glucose oxidation over glycolysis and induces apoptotic death of tumor cells. The present study investigated the potential of DCA to increase the antitumor effects of platinum- based compounds against a panel of permanent cell lines, including small cell lung cancer (SCLC), ovarian cancer, and Ewing’s sarcoma in vitro.MethodsDCA at a concentration of 10 mM was combined with cisplatin, carboplatin, satraplatin, the satraplatin metabolite JM118, oxaliplatin, oxoplatin, and picoplatin, and the cytotoxic activity was evaluated in proliferation tests employing a panel of different cell lines. Additionally, cells were pretreated with DCA and then exposed to the platinum drugs and etoposide, or incubated with cisplatin or etoposide followed by application of DCA, respectively.ResultsDCA 10 mM significantly increased the cytotoxicity of the platinum-based drugs carboplatin, satraplatin, JM118, and oxoplatin, but not cisplatin, picoplatin, and oxaliplatin in vitro. Preincubation of cell lines with DCA 10 mM for three days reduced the antiproliferative activity of platinum-based agents in sequential application, but exposure of cells pretreated with cisplatin or etoposide to DCA resulted in minor sensitization. The inhibitory effect of DCA showed no correlation with sensitization to the platinum compounds.ConclusionDCA alone in a concentration that shows low antiproliferative activity is capable of increasing the cytotoxicity of selected platinum compounds upon coincubation, and such combinations may be interesting for clinical application in tumors like SCLC, Ewing’s sarcoma, and ovarian cancer refractory to cisplatin chemotherapy as standard care. The mechanism of this synergistic effect of DCA in combination with specific platinum species remains to be investigated.

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Quantitative evaluation of dichloroacetic acid kinetics in human—a physiologically based pharmacokinetic modeling investigation

Cited by 19 publications

References 38 publications

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

In vitro cytotoxicity of combinations of dichloroacetate with anticancer platinum compounds

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