A superior alternative to Dichloroacetate (DCA)
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Diisopropylamine dichloroacetate (DADA) is a derivative of dichloroacetate (DCA), both acting as inhibitors of pyruvate dehydrogenase kinase (PDK). This inhibition shifts cancer cell metabolism from glycolysis (the Warburg effect) toward oxidative phosphorylation by activating pyruvate dehydrogenase (PDH), reducing lactate production and glucose uptake
Potency Against Lactate and Warburg Effect
DADA demonstrates superior inhibition of lactate production and warburg like glucose uptake compared to DCA in breast cancer cell lines like MDA-MB-231. At 10 mM, DADA reduced lactate to 20.7 mmol/L versus 28.9 mmol/L for DCA after 48 hours, with even greater differences at higher doses or longer exposures. In vivo, 100 mg/kg (0.0004 mol/kg) DADA suppressed tumor growth more effectively than an equimolar double dose of DCA (0.0008 mol/kg), inducing necrosis, reduced Ki67 proliferation, and autophagy leading to cell death.DADA exhibits lower cytotoxicity in non-tumor cells (e.g., no toxicity at 20 mM in ECV304 and MCF 10A lines) and better oral bioavailability, suggesting a wider therapeutic window than DCA, which can cause neurotoxicity and other dose-limiting effects at higher concentrations.Thiamine as an Analog to DCA
Thiamine (vitamin B1) acts analogously to DCA by enhancing PDH activity through its cofactor role (as thiamine pyrophosphate, TPP), countering PDK-mediated inactivation and mitigating the Warburg effect with reduced lactate/pyruvate ratios. Unlike DCA's direct PDK inhibition, thiamine supports mitochondrial metabolism more gently, avoiding DCA's risks like peripheral neuropathy or hepatotoxicity. Potential of DADA + Thiamine Combo
Combining DADA with thiamine could synergize PDH activation—DADA's potent PDK blockade paired with thiamine's cofactor replenishment—potentially yielding superior Warburg effect reversal over DCA alone. This approach might amplify aerobic metabolism, lactate reduction, and anti-tumor efficacy while minimizing side effects through complementary, low-toxicity mechanismsDiisopropylamine dichloroacetate (DADA) has been marketed there under the brand name Liverall (by Daiichi Sankyo) since the early 1960s for treating chronic liver conditions like fatty liver and hepatitis. It's approved for over 50 years of clinical use in hepatoprotection . Research also explores its PDK4 inhibition for metabolic benefits, such as in influenza models.
Key Uses
Primarily prescribed for fatty liver and hepatitis. Functions by inhibiting PDK4 to boost pyruvate dehydrogenase activity and ATP production -
@user73636 said in A superior alternative to Dichloroacetate (DCA):
Diisopropylamine dichloroacetate
Dimethylglycine may convert into this
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@alfredoolivas sounds interesting. Do you have any links on that?
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@user73636 Quoting Wikipedia:
https://en.wikipedia.org/wiki/Diisopropylamine_dichloroacetate#:~:text=DADA is formed by combining diisopropylamine with dichloroacetic acid. It is chemically related to pangamic acid (formerly known as "vitamin B15")%2C which may convert to DADA and diisopropylamine in the body.[4]Pangamic acid = ester of D-gluconic acid (the sugar-acid part) N,N-dimethylglycine (DMG) (the amino-acid part)
Pangamic acid, stomach acid quickly breaks the ester bond and you get free DMG + free gluconic acid.
