Home > antiangiogenic, apoptosis, chemo-sensitizer, melanoma, Uncategorized > Disulfiram (Antabuse) for cancer

Disulfiram (Antabuse) for cancer

Disulfiram (Antabuse) is an old thiocarbamate drug known to support the treatment of alcoholism and cocaine dependency. Unlike Naltrexone which is also used for alcoholism, its potential usefulness is cancer is well researched but curiously little publicized (Naltrexone is conversely little researched and well publicized ! Will discuss in this blog).  I am in fact quite impressed by the numerous documented investigations into Disulfiram’s use as an anti-cancer when I first investigated its potential in this area.

Schirmer and Scott seemed to have been the earliest to notice a relationship of disulfiram and tumor inhibition (Trans Am Assoc Genitourin Surg. 1966;58:63-6.), and subsequently Wattenberg was able to demonstrate that the dietary disulfiram inhibited DMH chemical induction of bowel cancer in mice  (JNCI, 1975 Apr;54(4):1005-6). Eventual research since the 70s have demontrated that disulfiram can block the P-glycoprotein extrusion pump and thus reduce drug-resistance, inhibits the transcription factor nuclear factor-kappaB, reduces angiogenesis, and inhibits tumor growth in cell lines and rodents.

Now where is the evidence?

a) In Vitro (cellular evidence):

Disulfiram inactivates the ability of the Rous sarcoma virus to malignantly transform chick embryo cells.

Disulfiram potentiated the cytotoxicity of nitrogen mustard and 5FU chemotherapy effects on leukemia and colorectal cells respectively.

Disulfiram can potentially reduce P-glycoprotein (P-gp) mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation (JNCI 2000 Jun 7;92(11):898-902).

Disulfiram induces apoptosis in melanoma cells (Mol Cancer Ther 2002 Jan;1(3):197-204).

Disulfiram inhibited invasion and angiogenesis of both tumor and endothelial cells possibly via interactions with MMP-2 and MMP-9 and inhibiting their proteolytic activity through a zinc related mechanism (Mol Pharmacol 2003 Nov;64(5):1076-84).

Disulfiram, as a member of the metal-chelating group of dithiocarbamate compounds, is able to bind with tumor cellular copper, forming an active complex with proteasome-inhibitory, apoptosis-inducing and anti-cancer activities. (Int J Mol Med 2007 Dec;20(6):919-25)

Disulfiram inhibited expression of metalloproteinases MMP-2 and MMP-9 and suppressed the invasion of human osteosarcoma cells. (J. Biochem Mol Biol 2007 Nov 30;40(6):1069-76)

b) In Vivo (animal evidence)

Dietary disulfiram inhibits chemical induction of intestinal (colon), bladder and breast cancer in rodents.

Disulfiram reduced ifosfamide-induced nephrotoxicity in rodents.

Disulfiram potentiated the cytotoxicity of nitrogen mustard chemotherapy in rodents (Cancer Res. 1989 Dec 1;49(23):6658-61).

c) Clinical (human experiences)

Roemeling et al. reported that human beings given 2 g of oral disulfiram at a particular time of day and high doses of cisplatin had lesser kidney toxicity. Disulfiram administration also apparently does not interfere with the antineoplastic activity of cisplatin (Chronobiol Intl 1986;3(1):55-64). Based on such evidence, a phase I and II study of cisplatinum and disulfiram was carried out which however overturned the hypothesis that disulfiram afforded nephroprotection in platinum chemotherapy (Am J Clin Oncol. 1990 Apr;13(2): 119 -24).

More recently in 2004, a first clinical report using a combination of oral zinc gluconate and disulfiram at approved doses for alcoholism induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects.

There is currently ongoing clinical trials of disulfiram with copper gluconate against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).

My take

This drug long known as a treatment for alcoholism found recent revival of interest as an anticancer and this has recently been reviewed by ZE Sauna et al. of the National Cancer Institute (Mol Biosyst 2005 Jul; 1(2): 127-34.  Epub 2005 May 26.)  Although there are no significant completed clinical trials to mention, both in vitro and animal data are supportive of its use, especially in melanoma and in conjunction with certain chemotherapies (eg 5FU), in cases of potential chemo-resistance, and as an anti-angiogenic perhaps in conjunction with Zinc gluconate.

It is not a totally hassle- free drug to prescribe though:

The initial dose is 500 mg for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg–500 mg) per day. The total daily dosage should not exceed 500 mg.  It is known to be a drug with moderate side-effects.  Of course, side-effects could be provoked if taken with alcohol, hence its use to support detox for alcohol dependence.  But other significant side-effects include hepatitis (1 case in 30,000 treated/yr), and neurologic. There are rare reports of psychosis and confusional states and peripheral nse effects, tiredness, headache and sleepiness are the most common.  Due to its CNS activity, drug-drug interaction is also an issue:

Drugs that may interact with disulfiram include, but are not limited to:

  • Bupropion (Wellbutrin IR/SR/XL, Amfebutamone)
  • Amphetamines (Adderall, Dexedrine, etc.)
  • Methylphenidate (Ritalin, Concerta, Focalin, etc.)
  • Cocaine (Occasionally used in dental procedures, and a known substance of abuse.)

The metabolism of other drugs may be inhibited by disulfiram, increasing their potential for toxic effects. Drugs known to have adverse effects when used concurrently with disulfiram include amitriptyline, isoniazid, and metronidazole (all with acute changes in mental state), phenytoin, some benzodiazepines, morphine, pethidine, and barbiturates.

  1. Michele
    November 11, 2009 at 5:13 pm

    Can anyone explain the anti-cancer properties of bromelain and other proteolytic enzymes as they relate to the anti-cancer activities of a proteasome inhibitors (in other words proteases have shown anti-cancer activity as have protease inhibitors) Would it be logical to conclude that digestive enzymes would be contra-indicated with disulfiram?

    Proteolytic enzymes (usually referring to the digestive enzymes such as amylase or lipase etc), protease inhibitors and proteasome inhibitors are quite distinct. Proteasome inhibitors are drugs that block the action of proteasomes, which are cellular complexes that break down proteins, like the p53 protein. But then Protease inhibitors (also known as PI’s, block proteases eg HIV protease) are usually referring to antibiotics or antivirals which for example inhibit HIV protease-1, and some of these agents (eg Nelfinavir) are being investigated (test tube testing stage) for cancer. It is easy to get all these mixed up because they sound similar, but they are not referring to the same drugs or family of drugs or compounds … hope this helps – RC

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