OneVan ha scritto:
E' potenzialmente cancerogeno, anche se per ora ciò è stato rilevato solo negli animali, magari lo è meno dei farmaci chemioterapici (a parte che anche questo potrebbe venir considerato chemioterapico alla fin fine...) non ci sono dati.
Comunque sembra promettente per cui speriamo bene.
These results show that lower doses of DCA could, at least in theory, be given to cancer patients while avoiding some of the damaging side effects seen at higher doses. For example, a clinical trial of DCA for a childhood disease found that the drug caused significant side effects, affecting the nervous system. It is also known to be an environmental pollutant. And researchers have found that DCA can actually cause cancer in animals.
Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia
Abstract
We examined the effect of hypoxia on apoptosis of human colorectal cancer (CRC) cells in vitro and in vivo. All cell lines tested were susceptible to hypoxia-induced apoptosis. DCA treatment caused significant apoptosis under normoxia in SW480 and Caco-2 cells, but these cells displayed decreased apoptosis when treated with DCA combined with hypoxia, possibly through HIF-1α dependent pathways. DCA treatment also induced significantly increased growth of SW480 tumor xenografts, and a decrease in TUNEL positive nuclei in hypoxic but not normoxic regions of treated tumors. Thus DCA is cytoprotective to some CRC cells under hypoxic conditions, highlighting the need for further investigation before DCA can be used as a reliable apoptosis-inducing agent in cancer therapy.
http://www.cancerletters.info/article/S0304-3835%2810%2900251-X/abstract
Toxicological Review Of Dichloroacetic Acid, 1998, p. 29/192:
To date, there have been no reports of DCA-induced neoplasia in any tissue or gonadal toxicity in humans.
http://www.epa.gov/iris/toxreviews/0654tr.pdf
Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.
Abstract
The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n > or = 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.
http://www.ncbi.nlm.nih.gov/pubmed/19543830
Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors.
Abstract
It has been reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth). Furthermore, omeprazole (OMP) is a well-known agent that enhances the effects of anticancer drugs. The aim of this study was to find clinically-used drugs that enhance the effects of DCA. The combination of DCA and OMP exhibited a more potent antitumor activity than DCA alone in HT1080 fibrosarcoma cells and RKO colon cancer cells, while the drugs did not affect the proliferation of WI-38 human fibroblasts. The inhibitory effect of DCA combined with OMP was reversed with vitamin E and Z-VAD-FMK; therefore conventional caspase-dependent cell growth inhibition through superoxide production was suggested as the mechanism for inhibition. The combination of these drugs also had an effect on HT1080 fibrosarcoma cells inoculated into mice. Since OMP and DCA may be administered orally and have been used clinically for several years without major side effects, we believe that this combination therapy could be readily translated to treat malignant tumors.
http://www.ncbi.nlm.nih.gov/pubmed/22740984
Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage.
Abstract
Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.
http://www.ncbi.nlm.nih.gov/pubmed/22866174
So where does DCA sit now, five years after the original excitement? Stalled, due to lack of interest, according to Dr. Michelakis. "We have not initiated another clinical trial with DCA in cancer," he told me in an email this week, "It was my hope that other centres, independent of us, will be inspired to do similar trials, but I have not seen any signs that this is the case."
"I am also disappointed that other investigators have not been interested to test this drug with proper trials on their patients," he added, "but I understand that without funding (although DCA itself is very cheap) this is very difficult. As I had said in the beginning of this work, taking a generic drug to patients with a deadly disease is as difficult a task as one can imagine in modern medicine, and it requires many people to participate and push the agenda. One person in one centre cannot do it."
http://www.cbc.ca/news/health/story/2012/05/28/cancer-drugs-experiments-crowe.html
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