(Note, not deuterium depleted but deuterium-enriched water improved anticancer efficacy of celecoxib)
https://www.preprints.org/manuscript/202305.2032/v1
Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Accumulating clinical and experimental evidence suggests the role of cyclo-oxygenase (COX) enzymes in the pathogenesis of cancers including HCC. Deuterium-enriched water (DEW) and deuterium-depleted water (DDW) play a role both in the treatment and prevention of cancers. Combination therapy using COX-inhibitors and DDW/DEW could be a rational strategy to enhance the cytotoxicity of either agent in HCC. The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW or DEW was determined in the Hep-G2 HCC cell line by MTT assay. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins, and caspase-3 activity were determined by SDS-PAGE and western blot. Co-treatment of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of Hep-G2 cells. These events were associated with the activation of p38 and JNK MAPKs and a decrease in pro-survival proteins Bcl-2, COX-2, and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it. The combination of DEW with NSAIDs might be effective against HCC cells by influencing principal cell signaling pathways, and this has a potential to become a candidate for chemotherapy.
That is so weird..... deuterium ENRICHED!!!!!!! I can't wait for more studies on this. I take celecoxib. Don't even know how one would get such water, hahah.
Yeah, that was a surprise, Rosaleen. They mention the concentration of DEW water (heavy water) in the study, maybe a pharmacist could prepare the solution?
Good to hear you´re already taking advantage of the synergy between celecoxib and PDE5 inhibitors, I really like celecoxib because it offers so many ways to boost anticancer efficacy (luteolin, aspirin, doxy, etc.)
Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis
https://www.spandidos-publications.com/10.3892/ijo.2020.5011
Abstract
Metastasis is a leading cause of mortality and morbidity in cancer. Urokinase (uPA), only expressed by the highly invasive cancer cells, has been implicated in invasion, metastases, and angiogenesis of several malignancies including breast cancer. Because uPA expression is strongly correlated with its hypomethylated state, we utilized the uPA gene in the highly invasive MDA-231 human breast cancer cells as a model system to test the hypothesis that pharmacological reversal of the uPA promoter hypomethylation would result in its silencing and inhibition of metastasis. S-Adenosyl-l-methionine (AdoMet) * has previously been shown to cause hypermethylation and inhibit demethylation. Treatment of MDA-231 cells with AdoMet, but not its unmethylated analogue S-adenosylhomocysteine, significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and metastasis in vivo. The effects of AdoMet on uPA expression were reversed by the demethylating agent 5'-azacytidine, supporting the conclusion that AdoMet effects are caused by hypermethylation. Knockdown of the methyl-binding protein 2 also causes a significant inhibition of uPA expression in vitro and tumor growth and metastasis in vivo. These treatments did not have any effects on estrogen receptor expression, suggesting that inhibition of hypomethylation will not affect genes already silenced by hypermethylation. These data are consistent with the hypothesis that hypomethylation of critical genes like uPA plays a causal role in metastasis. Inhibition of hypomethylation can thus be used as a novel therapeutic approach to silence the pro-metastatic gene uPA and block breast cancer progression into the aggressive and metastatic stages of the disease.
* S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet
" Our data also showed that AKG supplementation inhibited the glycolysis pathway as indicated by decreased mRNA expression of phosphofructokinase (Pfkl), aldolase fructose-bisphosphate A (Aldoa), and lactate dehydrogenase A (Ldha) (fig. S1L). "
