Chloroquine is an anti-malarial drug available at pharmacies for people travelling to area with malaria risks as well as to address other health challenges.
Note: based on a RGCC chemosensitivity analysis I have seen at a German clinic, Hydroxychloroquine has been effective in killing the cancer cells of 5 out 7 patients that were tested.
It is one of very few available drugs that inhibits autophagy, a mechanism associated with its anticancer properties. However, note that Chloroquine has other properties as well that may be very well related to anti cancer mechanism, such as zinc ionophore, and others (see below the section on mechanisms).
In cancer, authophagy is the process used by cancer cells to “self-eat” in order to survive. This is why authophagy can be both good and bad. Specifically, if authophagy is prolonged this will become a lethal process to cancer. On the other hand, for a short while (e.g. during chemotheraphy, radiotheraphy, etc.) authophagy is used by cancer cells to survive. Indeed, one of the mechanisms responsible for survival of the therapy-resistant hypoxic cells is (macro-) autophagy: a phenomenon in which cells provide themselves with energy (ATP) by digesting their own cell-organelles.
Therefore, if we can induce somehow a sustained authophagy process, theoretically cancer cells will end up consuming themselves and finally tumors will be gone. However, in realty I think this is challenging to achieve. What we can do on the other hand is to attack cancer cells with various treatments such as Salinomycin, 3BP, Diflunisal, B17, Chemotheraphy, Radiotheraphy, Vitamin C, etc. while starving the cancer cells via e.g. diet and medication, and at the same time use Chloroquine to inhibit the process through which the cancer cells will try to eat themselves during the treatment in order to survive. Indeed, Chloroquine is a potent blocker of autophagy and has been demonstrated in a lab setting to dramatically enhance tumor response to radiotherapy, chemotherapy and even anti-hormonal therapy (please see references below).
This is why Chloroquine has become part of many clinical trials, in combination with chemotherapy and other form of cancer treatments. The results are promising: “The results are very encouraging — striking, even says senior author Ravi Amaravadi, MD, an assistant professor of Medicine at Penn’s Abramson Cancer Center. Temsirolimus by itself has little effect in this patient population. Tumors laugh at it, with response percentages of just zero to 5 percent. But by combining it with hydroxychloroquine, we found that 14 out of 21 patients had stable disease after treatment, including five out of six melanoma patients.” (Ref1)
Its anticancer properties are relevant for most cancers. Therefore, this drug can be part of an anti-cancer drug cocktail and I would consider it as an addition next to chemo and/or radiation treatment. However, whenever considering to add to a chemo treatment just perform a short google check of the specific chemo and Chloroquine combo to make sure there is no study indicating antagonism.
Update August 1st 2019: Due to it’s antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious activity, Hydroxychloroquine will be used in French hospitals to possibly induce prevention of recurrent miscarriage (Ref.).
Update March 12th, 2020: Hydroxychloroquine has been shown to be effective against Coronavirus.
More specifically, there are several scientific publications indicating that:
- Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro – this study was published very recently (February 2020) and indicates that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection. In addition to this antiviral activity, chloroquine has an immune-modulating activity which may work in synergy with its antiviral activity.
- Coronavirus puts drug repurposing on the fast track – a Nature publication at the end of February 2020 indicates that Chloroquine or hydroxychloroquine has been selected for clinical trials in patients infected with Coronavirus
- In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – a publication from March 2020 indicating that Hydroxychloroquine was more potent than Chloroquine. The publication further proposes the following treatment schedule: “a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection”. Typically, the pills have 200mg. That means 2 pills 2x/day first day, followed by 2 pills/day during the coming days.
- For more discussions on COVID19 and a long list of relevant supplements and drugs please read this post
Case Reports and Clinical Trials in Cancer
Update Dec 2019: Case report: stage 4 pancreatic cancer to remission using paricalcitol and hydroxychloroquine in addition to traditional chemotherapy by Stephen Bigelsen: I am a physician specializing in Allergy and Asthma, who in July 2016, had tumors in the head and the tail of the pancreas with scattered peritoneal metastases and a CA19-9 of 11,575 U/mL. Working with physicians from Weill-Cornell and Johns Hopkins, I began treatment with gemcitabine and capecitabine, plus IV Paricalcitol (25 mcg 3x’s/week) and hydroxychloroquine (600 mg BID). These are both safe and inexpensive treatment options that have shown success in pre-clinical models, phase 2 human trials, and are readily available. I have now enjoyed a complete response with my latest CA19-9 of just 15 U/mL and no evidence of active disease on my most recent CT scan.
Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells that promote growth and survival of the tumor. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer cells.
Here is a longer list of clinical trials including Hydroxychloroquine: List
- Endosomal Acidification Inhibitor: Chloroquine is a lysosomotropic agent that prevents endosomal acidification . It accumulates inside the acidic parts of the cell, including endosomes and lysosomes. This accumulation leads to inhibition of lysosomal enzymes that require an acidic pH, and prevents fusion of endosomes and lysosomes. Chloroquine is commonly used to study the role of endosomal acidification in cellular processes, such as the signaling of intracellular TLRs. Moreover, Chloroquine inhibits autophagy as it raises the lysosomal pH, which leads to inhibition of both fusion of autophagosome with lysosome and lysosomal protein degradation. http://www.invivogen.com/chloroquine
Trapped as cationic species in the acidic organelles owing to his basic pKa, thereby elevating the endosomal pH. http://europepmc.org/articles/PMC3486884
It disburses quickly throughout the body and tends to reside primarily in the lysosomes, the so-called digestive organelles of cells. Lysosomes are involved with how cells dispose of waste material, including from the cell itself. In that role, they are important in the process of autophagy, where a cell under stress in desperate need of nutrition begins to feed upon itself. Autophagy is one way of killing cancer cells. Ref.
- Chloroquine is a zinc ionophore. http://www.ncbi.nlm.nih.gov/pubmed/25271834
- May also interfere with Iron: http://www.jci.org/articles/view/115301
- Chloroquine is a 4-aminoquinilone. The 4-aminoquinolones act by intercalation into the DNA of parasites http://pdfdrug.com/l/lfi-th.com1.html
- Another proposed mechanism involves breakdown of hemoglobin by the parasite and binding of chloroquine to ferriprotoporphyrin IX causing membrane damage. http://pdfdrug.com/l/lfi-th.com1.html
- Lowers intracellular pH and increases Ca release in cytoplasm from intracellular organelles: “When parasites are exposed to chloroquine, the cytosolic pH decrease as a result of extrusion of protons from acidic compartments and the parasites (P. falciparum) try to restore the cytosolic pH level using plasma membrane mechanisms (Saliba & Kirk 1999, Marchesini et al. 2000, Saliba et al. 2003). By using microphysiometry we showed that addition of chloroquine to P. chabaudi at the trophozoite stage led to a dose-dependent increase in the extracellular acidification rate (Fig. 6). The mean 50% maximal effective concentration (EC50) for three experiments was 16.29 ± 0.4 µM (n = 3) of chloroquine. This data reveal an activation of plasma membrane mechanism of protons extrusion under chloroquine treatment.”
“We have previously shown that the acidic pool also functions as a Ca2+ store in permeabilized malaria parasites and that chloroquine causes Ca2+ release from this store (Passos & Garcia 1998). In the present study, intact parasites were labeled with the calcium indicator, Fluo-3 AM to measure parasite cytosolic Ca2+ mobilization, and we also investigated the acidic pools in intact parasites within the RBC, using confocal microscopy.” Ref
Although in theory the side effects can be multiple, this drug is used by many people while traveling in countries with malaria risks.
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Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject’s weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg. Taken orally once a day. Administration during or after meals. (6.5 mg/kg will lead to about 400mg/day for most people.)
Some clinical trials are increasing the daily dose up to 1000mg but I woudl not go that high. The highest I would go would probably be 600mg/day.
Adding Zinc may help: We report that chloroquine is a zinc ionophore, which targets zinc to the lysosomes, and that the combination of zinc and chloroquine enhances their cytotoxicity and induces apoptosis in a human cancer cell model system Ref.
Note: hydroxycloroquine has a long half-life (32-56 days) in blood and a large volume of distribution (Ref). In other words, the max time required to be totally out of the blood may be up to 112 days!
Source & Cost
Other Name: Plaquenil, etc.
Can be ordered from pharmacy including online pharmacies such as this one. Here you have to say that you are going to a country like Haiti and pick a specific location in that country using Google maps as they will check that, 6 months trip should be equal with about 6 boxes for one person.
There are many pharmacies that are selling Chloroquine – so if you want it you will be able to find it at one of these pharmacies.
Synergists & Antagonists
Chloroquine can interact with Etoposide: http://www.finom.fi/syopajahappamuusihmisessa.pdf
- Indeed there is a study showing that Chloroquine stops the action of Etoposite in cells that are surrounded by normal pH (such as normal cells) and allows Etoposite to work in cells that are surrounded by acidic environment (such as cancer cells). So based on this, the authors suggest that Chloroquine could be used to lower the side effects of Etoposite (on normal cells) and be able to increase the dose of Etoposite and target better cancer cells. https://cancerres.aacrjournals.org/content/canres/54/11/2959.full.pdf
Adding Zinc may help: We report that chloroquine is a zinc ionophore, which targets zinc to the lysosomes, and that the combination of zinc and chloroquine enhances their cytotoxicity and induces apoptosis in a human cancer cell model system Ref.
Verapamil may enhance effectiveness by inhibiting Choloquine efflux from cancer cell: http://www.sciencedirect.com/science/article/pii/0169475888901597
Tetrandrine will do the same or better job as Verapamil at inhibiting MDR resistance http://www.malariajournal.com/content/12/1/117
Chloroquine seems to work well with Salinomycin http://www.sciencedirect.com/science/article/pii/S0167488913001717
Since you are here:
You may want to have a look at a summary of this website. You will find so many more interesting repurposed rugs for cancer https://www.cancertreatmentsresearch.com/summary-of-this-website/
Researchers Say Malaria Drug Could Also Treat Cancer: http://www.voanews.com/content/researchers-say-malaria-drug-could-also-treat-cancer-142693195/180326.html
Autophagy as a target for cancer therapy: new developments http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474143/
Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy.
Chloroquine is a zinc ionophore. http://www.ncbi.nlm.nih.gov/pubmed/25271834
Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine’s cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine’s anticancer activity.
Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. http://www.jci.org/articles/view/115301
Chloroquine and ammonium chloride, by virtue of their basic properties, have been shown to raise endocytic and lysosomal pH and thereby interfere with normal iron metabolism in a variety of cell types, including mononuclear phagocytes. Cellular iron metabolism is of critical importance to Legionella pneumophila, an intracellular bacterial pathogen whose capacity to multiply in human mononuclear phagocytes is dependent upon the availability of intracellular iron. In view of this, we have studied the effects of chloroquine and ammonium chloride on L. pneumophila intracellular multiplication in human monocytes. Chloroquine, at a concentration of 20 microM, and ammonium chloride, at a concentration of 20 mM, inhibited L. pneumophila intracellular multiplication by 1.4 +/- 0.2 (SEM) logs and 1.5 +/- 0.2 logs, respectively. Chloroquine- and ammonium chloride-induced inhibition of L. pneumophila intracellular multiplication was completely reversed by iron nitrilotriacetate, an iron compound which is soluble in the neutral to alkaline pH range, but not by iron transferrin, which depends upon acidic intracellular conditions to release iron. Chloroquine had no major direct effect on L. pneumophila multiplication in artificial media except at extremely high concentrations (15,000-fold that which inhibited L. pneumophila multiplication in mononuclear phagocytes), and inhibition at such concentrations was not reversed by iron nitrilotriacetate. This study demonstrates that chloroquine and ammonium chloride inhibit the intracellular multiplication of L. pneumophila by limiting the availability of iron to the bacterium. It is possible that such a mechanism of action underlies chloroquine’s antimicrobial effect against other intracellular pathogens, such as the agents of malaria and tuberculosis.
Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984580/
Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared to cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in
Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients http://www.ncbi.nlm.nih.gov/pubmed/26375670
The results of reduced SUVmax without tumor volume reduction after two weeks of Rapa and HCQ treatment may indicate that non-proliferative glycolysis occurred mainly in the cancer associated fibroblast compartment, and decreased glycolytic activity was evident from Rapa + HCQ double autophagy modulator treatment.
Autophagy as a modulator and target in prostate cancer. http://www.ncbi.nlm.nih.gov/pubmed/25134829
Autophagy, or ‘self-eating’, is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.
Targeting autophagy in breast cancer. http://www.ncbi.nlm.nih.gov/pubmed/25114840
Macroautophagy (referred to as autophagy here) is an intracellular degradation pathway enhanced in response to a variety of stresses and in response to nutrient deprivation. This process provides the cell with nutrients and energy by degrading aggregated and damaged proteins as well as compromised organelles. Since autophagy has been linked to diverse diseases including cancer, it has recently become a very interesting target in breast cancer treatment. Indeed, current clinical trials are trying to use chloroquine or hydroxychloroquine, alone or in combination with other drugs to inhibit autophagy during breast cancer therapy since chemotherapy and radiation, regimens that are used to treat breast cancer, are known to induce autophagy in cancer cells. Importantly, in breast cancer, autophagy has been involved in the development of resistance to chemotherapy and to anti-estrogens. Moreover, a close relationship has recently been described between autophagy and the HER2 receptor. Here, we discuss some of the recent findings relating autophagy and cancer with a particular focus on breastcancer therapy.
The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition. https://www.ncbi.nlm.nih.gov/pubmed/?term=30967635
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell progenitors. Although current treatments, including chemotherapy and glucocorticoids, have significantly improved survival, T-ALL remains a fatal disease and new treatment options are needed. Since more than 60% of T-ALL cases bear oncogenic NOTCH1 mutations, small molecule inhibitors of NOTCH1 signalling; γ-secretase inhibitors (GSI), are being actively investigated for the treatment of T-ALL. Unfortunately, GSI have shown limited clinical efficacy and dose-limiting toxicities. We hypothesized that by combining known drugs, blocking NOTCH activity through another mechanism, may synergize with GSI enabling equal efficacy at a lower concentration. Here, we show that the clinically used anti-malarial drug chloroquine (CQ), an inhibitor of lysosomal function and autophagy, decreases T-ALL cell viability and proliferation. This effect of CQ was not observed in GSI-resistant T-ALL cell lines. Mechanistically, CQ impairs the redox balance, induces ds DNA breaks and activates the DNA damage response. CQ also interferes with intracellular trafficking and processing of oncogenic NOTCH1. Interestingly, we show for the first time that the addition of CQ to γ-secretase inhibition has a synergistic therapeutic effect on T-ALL and reduces the concentration of GSI required to obtain a reduction in cell viability and a block of proliferation. Overall, our results suggest that CQ may be a promising repurposed drug in the treatment of T-ALL, as a single treatment or in combination with GSI, increasing the therapeutic ratio.
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