First, I will start this post by wishing all the readers a Happy New Year full of health for you and your family, and a lot of success in everything you do! I also like to specifically thank to Ann who was the first visitor/friend this year to post a wish to all of us on this website.
Dichloroacetate (DCA), is probably one of the first anti cancer drugs I came across when starting to search for new effective drugs that can help fight cancer. After all these years, I believe even more in the potential behind DCA. This is because, I do know personally two people/friends who benefited from DCA treatment and are alive today due to DCA. And they used no other major treatments such as chemo. One of them is a man diagnosed >10 years ago with stage IV colon cancer and the other is a man diagnosed >5 years ago with stage IV lung cancer. And both of them are alive today.
It is true, after about >5 years their cancer came back and they succeeded to manage that with various elements including 3BP. Below I also intend to shortly discuss the mechanism through which some cancers responding may become resistant to DCA and possible routes to overcome that.
DCA has been extensively discussed, investigated and used in both alternative cancer treatment and academic world. With this post, I do not intend to consolidate all the extensive research on DCA. Instead, I will make a short summary with the most relevant points I am aware of and that need to be considered when DCA is used as an anti cancer treatment. Next to this post, a lot of relevant discussions on the use of DCA can be found at the following website: http://www.thedcasite.com
DCA is a white powder, the salt version of Dichloroacetic acid. Outside the oncology field, DCA is a drug known for many decades that has been considered for treatment of lactic acidosis. (Ref.1, Ref.2) DCA as an anti-diabetic and lipid-lowering drug (Ref), with potential for treating these conditions as well as myocardial and cerebrovascular ischemia (Ref.).
While known for long time, the potential of DCA in oncology has only recently begun to receive attention after major publications from the University of Alberta, Edmonton, Canada where the scientists were concluding the following: “Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.” (Ref.1, Ref.2), scientific publications that until today are cited by >100 other scientific publications. An explosion of press coverage followed that: https://www.youtube.com/watch?v=oq-oT8-2tC8; https://www.youtube.com/watch?v=8nTg53izwpE; https://www.youtube.com/watch?v=oq-oT8-2tC8; and so on …
Due to its mechanism of action DCA may be relevant to most types of cancers, including:
- breast cancer (Ref.1, Ref.2, Ref.3)
- colon and colorectal cancer (Ref.1, Ref.2)
- prostate cancer (Ref.)
- acute myeloid leukemia (Ref.)
- oral squamous cell carcinoma (Ref.)
- glioblastoma (Ref.)
- Ovarian cancer (Ref.)
- Neuroblastoma (Ref.)
- Lung cancer (Ref.)
- Non-Hodgkin’s Follicular Lymphoma (Ref.)
- and most of the other cancers …
Other positive effects:
- reduces pain in cancer (due to acidity lowering effects) (Ref.)
- reduced massive ascites in 50% of the patients without adjuvant chemotherapy (Ref.)
That next to the fact that is a low cost, low side effects and accessible to all people, makes DCA one of the drugs that can be tried by all cancer patients.
Even more, due to its mechanism of action, DCA supports chemotheraphy and radiotheraphy (increases Reactive Oxygen Species in cancer cells and reduces acidity around the tumors) (Ref.1, Ref.2). And even more, because the acidity around the tumor is reduced, the immune system can increase its activity in those specific areas.
But as you will see if you read the rest of this post, there are some more tricks that we need to use in order to increase the chance of DCA for effectiveness against cancer.
Case reports in humans:
Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy. https://www.ncbi.nlm.nih.gov/pubmed/27803917
A case is presented in which oral DCA therapy resulted in tumour stabilization of stage 4 colon cancer in a 57 years old female for a period of nearly 4 years, with no serious toxicity. Since the natural history of stage 4 colon cancer consists of steady progression leading to disability and death, this case highlights a novel use of DCA as a cytostatic agent with a potential to maintain long-term stability of advanced-stage cancer.
A Novel Form of Dichloroacetate Therapy for Patients With Advanced Cancer: A Report of 3 Cases http://alternative-therapies.com/at/web_pdfs/s202khan.pdf
Oral dichloroacetate sodium (DCA) is currently under investigation as a single agent and as an adjuvant for treatment of various cancers. One of the factors limiting its clinical use in a continuous oral regimen is a doserelated, reversible neurotoxicity, including peripheral neuropathy and encephalopathy. The intravenous (IV) route has a number of potential advantages, including (1) pulsed dosing to achieve higher concentrations than feasible with oral use, (2) a longer washout period to reduce the potential for neurotoxicity, and (3) a bypassing of the digestive system, which is particularly significant for advanced-stage cancer patients. Data were available on high-dose IV DCA (up to 100 mg/kg/dose) that have confirmed its safety, both in healthy volunteers and in critically ill patients, allowing the authors to begin offlabel treatment of cancer patients. In several of their patients treated with IV DCA, the authors observed clinical, hematological, or radiological responses. This article presents 3 cases with patients who had recurrent cancers and for whom all conventional therapies had failed: (1) a 79-y-old male patient with colon cancer who had liver metastases, (2) a 43-y-old male patient with angiosarcoma who had pancreatic and bone metastases, and (3) a 10-y-old male patient with pancreatic neuroendocrine carcinoma who had liver metastases.
Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. http://www.ncbi.nlm.nih.gov/pubmed/22580646?dopt=Abstract&holding=npg
DCA combined with OPZ and TAM exhibited more potent antitumor activity than DCA alone in HT1080 fibrosarcoma cells, but did not influence proliferation of WI-38 human fibroblasts. All these drugs induce caspase-dependent cell growth inhibition through superoxide production. Since they can be taken orally and have been used clinically without major side effects, it was thought that this combination therapy would be a readily translated strategy to treat malignant tumors. Under the patient’s consent these three drugs were prescribed to a 51-year old female cholangiocarcinoma patient to whom neither gemcitabine+S-1 nor adoptive immunotherapy with natural killer cells was effective. Disease progression was successfully blocked (the rise of serum CA19-9 value) for three months, also confirmed by CT.
Non-Hodgkin’s Lymphoma Reversal with Dichloroacetate https://www.hindawi.com/journals/jo/2010/414726/
In June 2007, a 48-year-old male patient, diagnosed with Stage 4 Non-Hodgkin’s Follicular Lymphoma (NHL), was treated for 3 months with conventional chemotherapy resulting in a complete remission. Almost one year later tumors returned in the nasopharynx and neck lymph glands. Refusing all suggested chemotherapies, the patient began self-administering dichloroacetate (DCA) 900 mg daily with a PET scan showing complete remission four months later. Since his last PET scan, May, 2009, he remains tumor-free from continuous DCA usage.
Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis http://www.journalmc.org/index.php/JMC/article/view/2456/1816
Here we present an observational case report of a 49-year-old female, non-smoker, having a poor performance status with non-small-cell lung cancer and leptomeningeal carcinomatosis (LMC), who upon introduction of oral dichloroacetate (DCA) survived approximately 64 weeks (454 days) following palliative whole brain radiation without the need for chemotherapy or further targeted therapy to specifically address the LMC. To our knowledge, this is the first case report incorporating the use of DCA in LMC. Our findings are discussed in the context of previously reported applications of DCA in malignancies of the central nervous system.
For those familiar with the cellular metabolism, the mechanism behind DCA’s anti cancer effect is relatively straight forward. At least the main one as we understand today. Here is in a few words how DCA works:
Source photo: (Ref.)
- Pyruvate dehydrogenase (PDH), is a complex of enzymes that converts cytosolic pyruvate to mitochondrial acetyl-CoA, the substrate for the Krebs’ cycle.
- However, in most cancers, another enzyme called Pyruvate dehydrogenase kinase (PDK) (a mitochondrial enzyme) is activated and results in the selective inhibition of PDH.
- As a result, instead of entering mitochondria, because PDH is inhibited, pyruvate can not go in so that it goes further down the glycolisis (fermentation) pathway and is finally converted in lactic acid
- DCA has the potential to inhibit PDK, so that PDH can function again
- When PDH works, pyruvate can be processed by mitochondria, so that the cell engine produces again energy (ATP) in a normal way and not via fermentation
- When mitochondria works it produces Reactive Oxygen Species (ROS) as well. And it is known that high levels of ROS (such as H2O2) can inhibit tumor growth and result in apoptosis.
- This is also the reason why, DCA helps chemo and radio therapy, since both of these treatment routes lead to increase of ROS. Normally, cancer cells produce a high level of anto oxidants to cope with the intracellular ROS, but once the ROS levell is to high (due to e.g. chemo and/or DCA) tumor cells will be killed.
Here are more details on how DCA works: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567082/
Indeed, it has been shown that Dichloroacetate treatment improves mitochondrial metabolism, and the pyruvate dehydrogenase activity and the amount of acetyl-CoA in mitochondria was significantly higher after DCA treatment (Ref.)
It has also been shown that DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment. (Ref.)
B1 vitamin and Alpha Lipoic Acid may act against cancer via similar mechanism as Dichloroacetate (Ref.1, Ref.2). However, I would not combine ALA with DCA. At least not in the IV form. Please read this comment to understand why https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy/#comment-4502
As discussed shortly above cancer cells may become resistant to DCA. Two of the major reasons for resistance (and how to address them) are discussed in the next section below. Another reason for Resistance suggested by some of the most relevant scientist in the field may be the fact that in time, due to increase alkalinity of cancer cell, mitochondria may become totally dysfunctional or non-existent, in which case no matter how much DCA we would use, there will be no way for it to work (Ref: private communications).
Even when DCA can not effectively activate oxidative respiration via the mechanism described above, it may be able to kill cancer cells via a different mechanism that leads to accumulation inside the cytoplasm of high levels of citrate which in turn leads to the inhibition of glycolysis and inactivation of P-glycoprotein (Ref.). Inactivation of P-glycoprotein means that the cancer cells will not be able to push out chemotherapy and as a result, this also means that DCA can nicely support chemotherapy. Having this mechanism in mind, we can also argue that DCA theraphy works hand in hand with the Citric Acid therapy I discussed in another post: Citric Acid
How to increase the chance DCA will do its job? This is the most interesting part of the post to me.
Transport of DCA inside the cancer cells is essential … and not always there:
Dichloroacetate-induced apoptosis in cancer cells requires sodium-coupled monocarboxylates transporter SLC5A8 (SMCT1). If the transporter is not expressed, cells may not accumulate the compound to levels sufficient enough to cause apoptosis. (Ref.)
Note that SMCT1 is the same transporter that is required for the anti-cancer effects of Butyrate supplements or Pyruvate.
However, SMCT1 it is epigenetically silenced in most tumour cells (Ref.), which could explain why high DCA concentrations should be used to achieve cytotoxicity in cancer cells. So, this is the reason why DCA doesn’t work for all cancers or if it works it is required at a high dose.
So the question is, how to reactivate SLC5A8 when that is inactive? Inhibitors of DNA methylation induce reactivation of SLC5A8. (Ref.) This means we need Inhibitors of DNA methylation. Fortunately, procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. (Ref.) This is great, since procaine is accessible (easy to find in German pharmacies), cheap and safe. Procaine is used in alternative cancer treatment clinics in combination with Natrium Bicarbonate IVs and is also the main component in the well known anti aging drug Gerovital.
Now it becomes very interesting to me. I just found this paper stating the following “Knowledge on the regulation of SMCT1 at the intestinal level is very scarce. SMCT1 has been found to be inhibited by some NSAIDs (ibuprofen, ketoprofen, fenoprofen, naproxen and indomethacin), phytochemicals (resveratrol and quercetin), TNF-α, oxidative stress, chenodeoxycholic acid and by the absence of gut commensal bacteria. On the contrary, SMCT1 was found to be stimulated by some other NSAIDs (diclofenac, meclofenamate and sulindac), by activin A and by the probiotic Lactobacillus plantarum.” (Ref.)
Why is this so interesting to me? That is because the paper indicates that Diclofenac increases SMCT1 … and here is a funny story: My friend, stage IV cancer patient that saw his lung cancer gone when using DCA, once said to me that long time ago he had so much pain from his cancer … but he did not wanted to take Morphine. Instead, he used a lot of Diclofenac. I remember he said he took so much Diclofenac every day, like candies. And this was probably the key for such a good response to DCA he had. Unfortunately, not everyone can take a lot of Diclofenac due to the side effects related to the stomach, known to be characteristic to NSAIDs.
As you can see from above, Quercetin, Resveratrol and Ibuprofen should be avoided while on DCA.
It has been previously shown that Sulindac can indeed support DCA treatment, but the mechanism was explained in a different way (Ref.). However, possibly the main reason for the synergy between the two is actually explained above.
Not only transporters but also GSTZ1 expression and chloride concentrations are relevant for DCA effectivness:
Here is a paper published in 2016 that I find very relevant for understanding how to further improve DCA effectivness: “GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate” (Ref.). This paper indicates the following.
- DCA is metabolized in the liver by the glutathione transferase zeta 1 enzyme (GSTZ1)
- During metabolism of DCA, a portion of the GSTZ1 can be irreversibly inhibited by DCA
slowing the clearance of subsequent doses of DCA
- However, chloride anions can inhibit DCA-induced GSTZ1 inactivation
- Some cancer cells (such as in breast cancer) over express GSTZ1 and confer resistance to the anti cancer effects of DCA
- In addition in tumors chloride anions level is often abnormally high compared to the surrounding tissue
- On this line, if the tumor expresses GSTZ1 and contains a high chloride anions level, the GSTZ1 will be stable, maintaining the resistance to DCA
- As a result, co-treatment with compounds to reduce GSTZ1 expression or chloride anions level will reduce the resistance to DCA
This means that now we are in search for GSTZ1 an/or chloride anion trasnport inhibitors. Here are a few of those:
- Etacrynic acid is a Cl(-)-ATPase inhibitor http://www.ncbi.nlm.nih.gov/pubmed/1839837
- Lansoprazole and Omeprazole inhibit chloride channels http://www.ncbi.nlm.nih.gov/pubmed/10711360
- Chlorotoxin found in scorpion venom (see my post on scorpion venom) can also inhibit chlorine channels https://en.wikipedia.org/wiki/Chlorotoxin
- Metformin also inhibits Cl channels: Metformin impairs the chloride current directly interacting with the extracellular portion of CLIC1 (chloride intracellular channel 1 – a transiently active channel essential for GBM growth). http://www.impactjournals.com/oncotarget/index.php?
On the other hand Bromide, iodide and sulfite also protected GSTZ1 from inactivation by DCA (Ref.). So we want to avoid them. Same counts for Quercetin that may increase chloride anion level in the cytosol (Ref.). Thus, while Quercetin has its own anti cancer effects, when using DCA is good to avoid its use.
Safety and Toxicity:
DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. This is the main potential side effect.
In the majority of patients using it, DCA is well tolerated. Side effects are mild but can include fatigue, confusion, memory loss, sedation, tremors, hallucination, agitation, depression, heartburn (oral), and nausea (oral) (Ref.)
DCA is metabolized in the liver and as a result caution is required when administering DCA in cases of compromised liver function.
Absorbed in the gastrointestinal tract and less than 1% of the total given dose is excreted in the urine; Metabolism of DCA occurs in the liver; DCA inhibits its own metabolism resulting in slower clearance from the body after multiple doses, which increases the potential for toxic effects; Although the halflife with the initial dose is less than one hour, this half-life increases to several hours with successive doses. There appears to be a plateau of this effect and DCA serum levels do not continue to rise with ongoing use (Ref.).
- Start with 10mg/kg/day and increase slowly to about 25mg/kg/day (others are going to higher doses but I prefer safety instead – 25mg/kg/day is well tolerated (Ref.)). If neurophathy is emerging, reduce the dose slightly to below that level where it occurred. Here you can calculate the dosage depending on your weight http://www.thedcasite.com/dca_dosage.html
- Use half of the dose in the morning and half in the evening
- To avoid neurophathy use DCA during 5days/week and stop for the other two (others are using 2 weeks ON and one week OFF scheme)
Update 12-March-2017: According to this article (Ref.) it is best to use the two weeks On and one week off scheme.
- Use DCA until no evidence of disease
- Preferably to drink by mixing the powder from capsule in water: https://www.youtube.com/watch?v=EbLqAFD7HaI. This is for better absorption.
- Up to 100mg/kg can be well tolerated (Ref.) I would however never jump to that high dose and start from 20mg/kg and best stop around max 70mg/kg max (Ref.). We used this dose with no issues but others may react differently.
- Injected in 250ml NaCl bag, administered during 45 to 60 min
- Administered 2x/week
DCA effect is dose dependent but there is a saturation level beyond which increasing the dose has no extra benefit (Ref.).
Additions to increase effectiveness or address potential side effects:
- Caffeine: anecdotally, caffeine would increase effectiveness – I do not understand the mechanism behind this other than improving the micro vessel circulation
- B1 Vitamine (thiamine) to reduce chance for neurophaty – some take 500mg/day, others up to 2500mg/day (Ref.). In addition B1 vitamin has its own anti cancer effect similar to that of DCA (Ref.1)
- Procaine, Diclofenac or Sulindac to increase SMCT1 (see above)
- Omeprazole 80mg/day to increase DCA effectiveness (see above)
- Scorpion venom to increase DCA effectiveness (see above)
- Metformin 1000mg to 1500mg/day (see above)
Buyers should be aware that some companies may be selling fake DCA. One owner of a web-based company has already been convicted of internet fraud for selling counterfeit DCA http://www.cbc.ca/news/story/2010/06/01/con-dca-gaber.html As a result take care where you are ordering your DCA. One reader of this website (Emad) seeing positive results with his mom while using DCA and chemo wrote the following: “I tried this www.puredca.com, and this www.dcalab.com but the best results i had is when using this one www.dcacancer.org“.
IV form can be purchased from compounding pharmacies such as those listed here https://www.cancertreatmentsresearch.com/?page_id=945. However, it may be too expensive compared to the self made version. Because DCA is water soluble it can be easily prepared in IV form in the same way as 3BP (see 3BP IV section here https://www.cancertreatmentsresearch.com/?p=47). Depending on the dose used, self made version will cost <10 euro / dose.
Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. https://www.ncbi.nlm.nih.gov/pubmed/?term=SLC5A8+dca
There has been growing interest among the public and scientists in dichloroacetate (DCA) as a potential anticancer drug. Credible evidence exists for the antitumor activity of this compound, but high concentrations are needed for significant therapeutic effect. Unfortunately, these high concentrations produce detrimental side effects involving the nervous system, thereby precluding its use for cancer treatment. The mechanistic basis of the compound’s antitumor activity is its ability to activate the pyruvate dehydrogenase complex through inhibition of pyruvate dehydrogenase kinase. As the compound inhibits the kinase at micromolar concentrations, it is not known why therapeutically prohibitive high doses are needed for suppression of tumor growth. We hypothesized that lack of effective mechanisms for the entry of DCA into tumor cells may underlie this phenomenon. Here we show that SLC5A8 transports DCA very effectively with high affinity. This transporter is expressed in normal cells, but expression is silenced in tumor cells by epigenetic mechanisms. The lack of the transporter makes tumor cells resistant to the antitumor activity of DCA. However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells and prostate cancer cells. Normal cells, which constitutively express the transporter, are however not affected by the compound, indicating tumor cell-selective therapeutic activity. The mechanism of the compound’s antitumor activity still remains its ability to inhibit pyruvate dehydrogenase kinase and force mitochondrial oxidation of pyruvate. As silencing of SLC5A8 in tumors involves DNA methylation and its expression can be induced by treatment with DNA methylation inhibitors, our findings suggest that combining DCA with a DNA methylation inhibitor would offer a means to reduce the doses of DCA to avoid detrimental effects associated with high doses but without compromising antitumor activity.
A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. http://www.ncbi.nlm.nih.gov/pubmed/17222789
The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.
Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate http://link.springer.com/article/10.1007/s10545-014-9808-2/fulltext.html
Pyruvate dehydrogenase complex (PDHC) is a key enzyme in metabolism linking glycolysis to tricarboxylic acid cycle and its activity is tightly regulated by phosphorylation catalyzed by four pyruvate dehydrogenase kinase (PDK) isoforms. PDKs are pharmacological targets for several human diseases including cancer, diabetes, obesity, heart failure, and inherited PDHC deficiency. We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected. Moreover, docking studies revealed putative binding sites of phenylbutyrate on PDK2 and 3 that are located on different sites compared to dichloroacetate (DCA), a previously known PDK inhibitor. Based on these findings, we showed both in cells and in mice that phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone. These results suggest that therapeutic efficacy can be enhanced by combination of drugs increasing PDHC enzyme activity.
Metabolic plasticity in cancer cells : involvement in the processes of proliferation and response to radiotherapy http://dial.uclouvain.be/handle/boreal:171100 http://dial.uclouvain.be/downloader/downloader.php?pid=boreal:171100&datastream=PDF_01
While pioneering studies suggested that enhanced glycolysis, a hallmark of cancer, was caused by an irreversible impairment in mitochondrial respiration, more recent data reported functional mitochondrial activity in many cancer cells. In this thesis, we thus intended to investigate whether metabolic modulations could improve the therapeutic outcome of cancer. We found that dichloroacetate, a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype, and decreased tumor cell proliferation through a decrease in the activity of the pentose phosphate pathway. In a second part of this work, we investigated whether targeting mitochondrial respiration with H2S, the last gaseous transmitter identified in mammals, improved tumor response to radiotherapy. By rapidly alleviating hypoxia inside solid tumors, the single injection of a H2S donor increased the radioresponse of cancer in mice. Overall, our thesis work emphasizes the ability of cancer cells to remodel their energetic metabolism in response to external stimuli and supports that both glycolysis and oxidative phosphorylation are attractive targets for cancer therapy.
Metabolic Modulation of Glioblastoma with Dichloroacetate http://stm.sciencemag.org/content/2/31/31ra34.abstract
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133+, nestin+ cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor–1α, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
Dichloroacetate and cancer: New home for an orphan drug? http://www.ncbi.nlm.nih.gov/pubmed/25157892
We reviewed the anti-cancer effects of DCA, an orphan drug long used as an investigational treatment for various acquired and congenital disorders of mitochondrial intermediary metabolism. Inhibition by DCA of mitochondrial pyruvate dehydrogenase kinases and subsequent reactivation of the pyruvate dehydrogenase complex and oxidative phosphorylation is the common mechanism accounting for the drug’s anti-neoplastic effects. At least two fundamental changes in tumor metabolism are induced by DCA that antagonize tumor growth, metastases and survival: the first is the redirection of glucose metabolism from glycolysis to oxidation (reversal of the Warburg effect), leading to inhibition of proliferation and induction of caspase-mediated apoptosis. These effects have been replicated in both human cancer cell lines and in tumor implants of diverse germ line origin. The second fundamental change is the oxidative removal of lactate, via pyruvate, and the co-incident buffering of hydrogen ions by dehydrogenases located in the mitochondrial matrix. Preclinical studies demonstrate that DCA has additive or synergistic effects when used in combination with standard agents designed to modify tumor oxidative stress, vascular remodeling, DNA integrity or immunity. These findings and limited clinical results suggest that potentially fruitful areas for additional clinical trials include 1) adult and pediatric high grade astrocytomas; 2) BRAF-mutant cancers, such as melanoma, perhaps combined with other pro-oxidants; 3) in which resistance to standard platinum-class drugs alone may be overcome with combination therapy; and 4) tumors of endodermal origin, in which extensive experimental research has demonstrated significant anti-proliferative, pro-apoptotic effects of DCA, leading to improved host survival.
Sensitization of breast cancer cells to paclitaxel by dichloroacetate through inhibiting autophagy http://www.sciencedirect.com/science/article/pii/S0006291X17309786
Chemotherapy is still the main adjuvant strategy in the treatment of cancer, however, chemoresistance is also frequently encountered. Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while the lack of effective and specific autophagy inhibitors hinders its application. Here we found that dichloroacetate (DCA), a small molecule compound, could significantly inhibit the autophagy induced by Doxorubicin in breast cancer cells. And DCA markedly enhances Doxorubicin-induced breast cancer cell death and anti-proliferation in vitro. But the sensitization to Dox of DCA was significantly reduced through induction of autophagy by rapamycin. Moreover, the combined therapy of Dox and DCA could significantly inhibit tumor growth in vivo and prolong mouse survival time. Taken together, we demonstrate that DCA could inhibit doxorubicin-inducing autophagy and provide a novel strategy for improving the anti-cancer efficacy of chemotherapy.
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