Apoptosis; ROS/Reactive oxygen species; PDHK; NKCC

In mitochondria, sodium dichloroacetate promotes the production of ROS. Sodium dichloroacetate influences cell viability and growth by increasing the production of reactive oxygen species (ROS) that arises from oxidative metabolism promotion. Pyruvate dehydrogenase kinases (PDK) inhibition, restored pyruvate dehydrogenase (PDH) activity, and the promotion of oxidative metabolism in conjunction with increased intracellular ROS production—all of which are dependent on the dosage of sodium dichloroacetate—were linked to the effects of sodium dichloroacetate on multiple myeloma cell viability, cell cycle arrest, and apoptotic cell death. In rat VM-M3 glioblastoma cells, the effects of sodium dichloroacetate combined with CI inhibition to promote oxidative stress. Elevated reactive oxygen species (ROS) in cancer cells treated with sodium dichloroacetate are linked to apoptosis induction brought on by elevated cytochrome c expression. T-cell differentiation is dependent on ROS and is induced by sodium dichloroacetate[1].

When male gonad-intact and castrated rats are treated with sodium dichloroacetate, the levels of NKCC1 RNA expression are markedly reduced; in contrast, no such effect is observed in female gonad-intact and castrated rats treated with sodium dichloroacetate[1]. In Wistar male rats, a single dose of sodium dichloroacetate results in a noticeably greater 24-hour diuresis; this increased diuresis is associated with NKCC2 inhibition. When comparing the kidneys of intact male and female Sprague-Dawley rats, the kidneys of intact female rats have more NKCC2 than the kidneys of intact male rats[1]. When male rats who are naïve are dosed 5, 20, and 100 mg/kg of sodium dichloroacetate orally, their bioavailability is significantly lower than that of rats whose GSTζ is depleted (10%, 13%, 81%, and 31%, 75%, 100%, respectively). Rats depleted of GSTζ exhibit linear kinetics for the liver extraction of sodium dichloroacetate; however, at higher doses, this process decreases with metabolism saturation[1].

Sodium dichloroacetate (DCA) is eliminated mainly through GSTζ-catalyzed dechlorination to glyoxylic acid, which is further metabolized by mitochondrial or cytosolic enzymes. Sodium dichloroacetate can also be dechlorinated to monochloroacetic acid in the blood. The metabolism of DCA in rodents decreases for prolonged administration as DCA expresses a fast effect in inhibiting its own metabolism after the first dosing, and an increased inhibition was noted after the second oral dosing in male rats by inhibiting GSTζ. In the pharmacokinetic model, measuring plasma DCA concentrations in naive and male rats and mice pretreated with 2 g/L DCA in drinking water, the estimated reduction in DCA metabolism among naive and 2 g/L pretreated rodents was 99% in rats and 76% in mice, showing significant species-related differences in DCA degradation. The rate constants for DCA-dependent GSTζ inactivation in mouse, rat, and human liver cytosol were different as rat > mouse > human [1].

Sodium dichloroacetate (DCA) affects cell growth and viability through the ROS production increase derived from the promotion of oxidative metabolism. The effects of DCA on multiple myeloma cell viability, cell cycle arrest, and apoptotic cell death were associated with PDK inhibition, restored PDH activity, and the promotion of oxidative metabolism in association with increased intracellular ROS production which depends on the DCA dose. The DCA effect cooperated with C I inhibition promoting the oxidative stress in rat VM-M3 glioblastoma cells. Increased ROS levels in DCA-treated cancer cells were related to the induction of apoptosis associated with the increased cytochrome c expression.[1]

It was reported that a single Sodium dichloroacetate (DCA) dose caused a significantly higher 24 h diuresis in Wistar male rats, and the increased diuresis was related to NKCC2 inhibition. Gender differences in renal NKCC2-related sodium handling have been noted in rats. The NKCC2 is more abundant in kidneys of intact females compared to intact males, with a greater transporter density in Sprague–Dawley female rats; ovariectomy suppresses this gender difference and17-β estradiol increases while progesterone decreases NKCC2 abundance in ovariectomized rats; these data support the suggestion that the lower the NKCC2 expression in male rat kidney, the more they are androgen-dependent. The DCA effect on NKCC2 might be related to DCA-induced ROS generation [1].

---

Pharmacokinetic studies in rodents and dogs demonstrated the clear time-dependent non-linear kinetics of Sodium dichloroacetate (DCA), with a high clearance decrease and high accumulation ratio after repeated dosing. The DCA distribution and plasma clearance in male animals following repeated dosing vary with species and age. Following the intraperitoneal administration of a single 38.5 mg/kg dose in male F344 rats, the hepatic level of GSTζ immunoreactive protein decreased to less than 40% of the control value: subsequently, 7–8 days were required for the return of the GSTζ protein level and DCA metabolism to control values. Studies in rats have demonstrated that changes in GSTζ activity are directly related to the elimination capacity and persistence of DCA. Following the administration of 50 mg/kg DCA, the elimination half-life was age-dependent: it was significantly shorter in male Sprague–Dawley rats aged 3–4 months than in those aged 16 months. The maximum DCA plasma level following two doses was higher than after a single dose, and the elimination half-life increased after the repeated dosing [1].

---

During the pharmacokinetics study, Fischer-344 male rats aged 8–10 weeks received 0.05–20 mg/kg of Sodium dichloroacetate (DCA) in naïve and GSTζ-depleted rats (GSTζ was depleted by exposing rats to 0.2 g/L DCA in drinking water for 7 days). The GSTζ depletion significantly slowed the elimination of DCA. The oral DCA bioavailability in naïve male rats dosed 5, 20 and 100 mg/kg was significantly lower than in GSTζ-depleted ones (10%, 13%, 81% and 31%, 75%, 100%, respectively). The liver extraction of DCA in the GSTζ-depleted rats had linear kinetics, but it decreased with the metabolism saturation at higher doses. Sodium dichloroacetate is unable to fully inhibit GSTζ activity in rats, and the existence of a portion of DCA intrinsic hepatic clearance free from DCA self-inhibition was suggested.

---

saline; 500 and 1000 mg/kg; i.p.

C57BL/6 mice

[1]. The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo. Cancers (Basel). 2019 Aug 20;11(8). pii: E1210.

Sodium Dichloroacetate is the sodium salt of dichloroacetic acid with potential antineoplastic activity. Dichloroacetate ion inhibits pyruvate dehydrogenase kinase, resulting in the inhibition of glycolysis and a decrease in lactate production. This agent may stimulate apoptosis in cancer cells by restoring normal mitochondrial-induced apoptotic signaling.
A derivative of ACETIC ACID that contains two CHLORINE atoms attached to its methyl group.

C2HCL2O2.NA

150.92

149.925

C, 15.92; H, 0.67; Cl, 46.98; Na, 15.23; O, 21.20

2156-56-1

517326

White to off-white solid powder

194ºC at 760mmHg

198 °C (dec.)(lit.)

0.196mmHg at 25°C

0

2

1

7

64.7

0

LUPNKHXLFSSUGS-UHFFFAOYSA-M

InChI=1S/C2H2Cl2O2.Na/c3-1(4)2(5)6;/h1H,(H,5,6);/q;+1/p-1

sodium;2,2-dichloroacetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.25 mg/mL (14.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.25 mg/mL (14.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.25 mg/mL (14.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 100 mg/mL (662.60 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)