Dichloroacetate (DCA) and IV Drip Therapy
Description:
Dichloroacetate (DCA) is a relatively small molecule that has been used as a treatment for lactic acidosis. It inhibits lactate formation by releasing pyruvate dehydrogenase kinase from negative regulation, promoting pyruvate entry into the TCA cycle. This leads to increased oxygen consumption and reactive oxygen species (ROS) formation, while glycolysis and lactate production are suppressed.
Non-cancerous human cells prefer the aerobic pathway for energy formation via the electron transport chain (ETC). However, cancer cells experience the Warburg Effect, where most glucose is converted to lactate, regardless of oxygen availability. By pushing cancer cells towards TCA/ETC use, DCA increases ROS formation and oxygen consumption, potentially leading to apoptosis in cancer cells.
Pharmacology
Mitochondrial Dynamics:
The mitochondrial membrane potential differs between normal and cancerous cells. In cancer cells, the membrane is hyperpolarized, making the cell resistant to apoptosis. DCA depolarizes both normal and cancer cells but preferentially leads to cancer cell apoptosis, sparing healthy cells. This effect is likely due to the difference in mitochondrial membrane potentials between cancerous and normal cells.
Activation of the p53 gene, among others, plays a key role in the membrane potential changes that trigger apoptosis. DCA has been shown to increase mitochondrial ROS (mROS) and activate p53 in glioblastoma (GBM) cells, leading to anti-proliferative and pro-apoptotic effects in both in-vitro and in-vivo studies.
Glutathione and DCA
The tripeptide glutathione (GSH) has multiple interactions with DCA metabolism. It is consumed during DCA metabolism, with GSH acting as a cofactor for 4-maleylacetoacetate (MAAI), which is depleted during this process. This depletion may contribute to DCA toxicity. On the other hand, NAC (N-Acetyl Cysteine) and ascorbate have been shown to enhance DCA’s activity.
Properly timed administration and restriction of GSH during DCA treatments can help balance their interaction. A recommended approach is to avoid administering GSH on days when DCA is used concurrently with oxidative therapies, while allowing GSH administration on non-treatment days.
Indications and Usage
Cancers Targeted:
DCA has shown potential in targeting cancers like glioblastoma (GBM), as it crosses the blood-brain barrier. Other cancer types that have shown sensitivity to DCA include breast, prostate, colorectal, pancreatic, and endometrial cancers.
Side Effects and Toxicity
The most common side effect of DCA is dose-dependent, reversible peripheral neuropathy. Other toxic effects may involve glutathione metabolism. To reduce the risk of side effects, DCA treatment is often paired with nutrient support, including glutathione and antioxidant supplementation.
IV Drip Therapy Integration
Integrating DCA with IV Drip therapy has proven effective for targeting cancer cells, particularly when combined with high-dose vitamin C and glutathione. This approach helps enhance mitochondrial function and reduces the oxidative stress that leads to cancer cell death.
Research and Future Directions
Research into DCA as a cancer therapy shows promise, particularly when combined with other supportive therapies. Future directions may explore further synergies between DCA and oxidative or glutathione-based treatments.