Dichloroacetate (DCA) inhibits aerobic glycolysis via inhibition of Pyruvate Dehydrogenase kinase (PDK), which allows for the phosphorylation of Pyruvate Dehydrogenase and the formation of acetylCo-A. This then feeds the krebs cycle. Increased mitochondrial activity increases ROS and resultant apoptosis of cancer cells.
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
The most important reason for the poor performance of cancer drugs is the remarkable heterogeneity and adaptability of cancer cells. The molecular characteristics of histologically identical cancers are often dissimilar and molecular heterogeneity frequently exists within a single tumour.
Because GO is far more efficient in generating ATP compared with GLY (producing 36 vs 2 ATP per glucose
molecule), cancer cells upregulate glucose receptors and significantly increase glucose uptake in an attempt to ‘catch up
early carcinogenesis often occurs in a hypoxic microenvironment, the transformed cells have to rely on anaerobic GLY for energy production.
Hypoxia-inducible factor (HIF) is activated in hypoxic conditions
evidence suggests that transformation to a glycolytic phenotype offers resistance to apoptosis
non-small cell lung cancer, breast cancer and glioblastoma
Dichloroacetate activated the pyruvate dehydrogenase, which resulted in increased delivery of pyruvate into the mitochondria
DCA increased GO and depolarised the mitochondria, returning the membrane potential towards the levels of the non-cancer cells, without affecting the mitochondria of non-cancerous cells
induction of apoptosis by DCA in non-small cell lung cancer, breast cancer and glioblastoma cell lines
DCA was shown to induce apoptosis in endometrial (Wong et al, 2008) and prostate (Cao et al, 2008) cancer cells
DCA induces apoptosis of endometrial cancer cells in cell line study. DCA is a pyruvate dehydrogenase kinase inhibitor which will increase apoptosis and decrease proliferation. DCA serves to recapture the mitochondrial kreb's cycle and ETC coupling potential.
DCA can penetrate into the traditional chemotherapy sanctuary sites. Interestingly, it was reported that DCA could penetrate across the BBB,30 exhibiting the potential activity for brain therapy.
Clinical studies of DCA have shown reduced lactate levels
It has been reported that DCA activates the PDH by inhibition of PDK in a dose-dependent manner, and results in increased delivery of pyruvate into the mitochondria
The antitumor activity of DCA on nonsmall cell lung cancer, breast cancer, glioblastomas, and endometrial and prostate cancer cells has been demonstrated
It is well known that many chemotherapeutic agents have a low therapeutic index in brain tumors.
The most common metabolic hallmark of cancer cells is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen
Pyruvate dehydrogenase kinase (PDK) is a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria
In the presence of activated PDK, pyruvate dehydrogenase (PDH), a critical enzyme that converts pyruvate to acetyl-CoA instead of lactate in glycolysis, is inhibited, limiting the entry of pyruvate into the mitochondria.
the level of Hsp70 was significantly decreased
DCA can penetrate the BBB
It has been reported that DCA treatment resulted in an increase in the proportion of tumor cells in the S phase, showing a decrease in proliferation as well as the induction of apoptosis
Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport, and/or stabilization by acting as a molecular chaperone, leading to the inhibition of apoptosis by both caspase-dependent and/or independent pathways
HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, and metastasis
Considering the fact that high expression of HSPs is essential for cancer survival, the inhibition of HSPs is an important strategy of anticancer therapy.
In addition, after 5 years of continued treatment with oral DCA at a dose of 25 mg/kg, the serum DCA levels are only slightly increased compared with the levels after the first several doses, also showing its safety for oral administration at this dose.
DCA can enter the circulation rapidly after oral administration and then generate the stimulation of PDH activity generally within minutes.
Our in vivo results in tumor tissues indicated that DCA significantly induced ROS production and decreased MMP in tumor tissues
The numbers of microvessels in the DCA treatment groups were significantly decreased, suggesting the potential antiangiogenic effect of DCA
Under hypoxic conditions, hypoxia-inducible factor (HIF-1α) is activated and induces angiogenesis
In addition, HIF-1α can also induce the expression of PDK,48 which can inhibit the activity of PDH
The inhibition effect of DCA on HIF-1α would decrease vascular endothelial growth factor and inhibit angiogenesis
the antiangiogenic effect in the 25 mg/kg treatment group was lower than that in 75 mg/kg or 125 mg/kg treatment groups
In conclusion, DCA induces the apoptosis of C6 cells through the activation of the mitochondrial pathway, arresting the cell cycle of C6 cells in S phase and down-regulating Hsp70 expression.
DCA significantly induced the ROS production and decreased the MMP in tumor tissues. Our in vivo antitumor activity results also indicated that DCA has an antiangiogenic effect
Tumor Microenvironment is hypoxia and acid which negates effects of therapies such as DCA. Alkalinization of the tumor micronenvironment is a means to open the tumor to the effects of therapies such as DCA.
alteration of pH regulators V-ATPase and MCT1, and other cell survival regulators such as PUMA, GLUT1, Bcl2 and p53
DCA as a cancer stabilizing agent
A protocol of natural medications was developed to address the dose-limiting neurologic toxicity, in collaboration with a naturopathic physician (Andrews). The oral DCA regimen that was developed included three natural medications acetyl L-carnitine[29-31], R-alpha lipoic acid[32-34] and benfotiamine[35-37], for the primary purpose of neuropathy prevention
measurable benefits from DCA therapy in 60%-70% of cases