nontoxic antialcolism drug found to cause apoptosis of breast cancer cells

[Lani]

They did not test her2+ cells however

Cancer Res. 2006 Nov 1;66(21):10425-33. Links
Disulfiram, a Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome Activity.

Chen D,
Cui QC,
Yang H,
Dou QP.
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
Disulfiram (DSF), a member of the dithiocarbamate family capable of binding copper and an inhibitor of aldehyde dehydrogenase, is currently being used clinically for the treatment of alcoholism. Recent studies have suggested that DSF may have antitumor and chemosensitizing activities, although the detailed molecular mechanisms remain unclear. Copper has been shown to be essential for tumor angiogenesis processes. Consistently, high serum and tissue levels of copper have been found in many types of human cancers, including breast, prostate, and brain, supporting the idea that copper could be used as a potential tumor-specific target. Here we report that the DSF-copper complex potently inhibits the proteasomal activity in cultured breast cancer MDA-MB-231 and MCF10DCIS.com cells, but not normal, immortalized MCF-10A cells, before induction of apoptotic cancer cell death. Furthermore, MDA-MB-231 cells that contain copper at concentrations similar to those found in patients, when treated with just DSF, undergo proteasome inhibition and apoptosis. In addition, when administered to mice bearing MDA-MB-231 tumor xenografts, DSF significantly inhibited the tumor growth (by 74%), associated with in vivo proteasome inhibition (as measured by decreased levels of tumor tissue proteasome activity and accumulation of ubiquitinated proteins and natural proteasome substrates p27 and Bax) and apoptosis induction (as shown by caspase activation and apoptotic nuclei formation). Our study shows that inhibition of the proteasomal activity can be achieved by targeting tumor cellular copper with the nontoxic compound DSF, resulting in selective apoptosis induction within tumor cells. (Cancer Res 2006; 66(21): 10425-33).

[Christine MH-UK]

This is one of a series of articles relating to tetrathiomolybdate, which is used against Wilson's disease:

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15892619

1: Curr Cancer Drug Targets. 2005 May;5(3):195-202.

Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.

Brewer GJ.

Department of Human Genetics, University of Michigan Medical School, 5024 Kresge
Bldg. II, Ann Arbor, MI 48109-0534, USA. brewergj@umich.edu

Tetrathiomolybdate (TM) is a novel anticopper agent under development for use in Wilson's disease. It acts by forming a stable tripartite complex with serum albumin and copper, rendering the complexed copper unavailable for cellular uptake. TM is a very potent anticopper agent and has an excellent safety profile. It has been shown that normal copper levels are required for optimal angiogenesis. Based on this background, we decided to evaluate TM as an anticancer agent. TM treatment of Her/2neu mice, genetically programmed to develop breast cancer, completely prevented the development of visible mammary cancers, although avascular microscopic clusters of cancer cells were present in the breasts of TM treated animals. Controls developed grossly visible tumors. TM was able to strongly inhibit tumor growth in six other rodent models. In a phase 1/2 clinical trial of advanced and metastatic cancers, freedom from progression averaged 11 months, and some individual results were quite dramatic. Eight phase 2 studies of specific cancers have been launched. TM's hypothesized mechanism of
action is inhibition of angiogenic cytokines. Unlike other current approaches to
antiangiogenic therapy which target single agents, we hypothesize that TM
inhibits multiple angiogenic cytokines. Part of this effect appears to stem from
inhibition of nuclear factor kappa B (NF(K)B), which in turn controls
transcription of many angiogenic and other cytokines. However, there are
probably multiple mechanisms, in that some angiogenic cytokines appear to have separate mechanisms of copper dependence. The inhibition of multiple angiogeniccytokines gives TM the potential to be a more global inhibitor of angiogenesis.

PMID: 15892619 [PubMed - indexed for MEDLINE]

[Lani]

this was truly relevant as I, perhaps stupidly (but always with good intent), attended a lecture at Stanford this week by David Baltimore a Nobel Prize winner and (until two months ago) President of CALTECH. It was WAY above my head in abbreviation (although he had nice slides with good diagrams with the names of all the abbreviations--compounds--and their place in the scheme of things) His lecture was on "CONTROL of NF K beta" They have found perhaps 25 pathways which feed into/out of it and he is sure they are only a small minority of them. It is a pathway that is conserved in nature--it is present in small worms, flies, rodents, etc in pretty much the same way and it is used by many systems involving wound healing, inflammation, embryogenesis, tumorigenesis.

Left feeling this was one system it would be hard to inhibit without throwing a monkeywrench in the system.

Left overwhelmed by how little we know (and this man has certainly done his part in increasing that!!)

Will pour over your article--thanks!

[Lani]

It suggests it will be best used in her2+ early breast cancer patients with micro or macroscopic lymph node involvement. A company has been formed and Phase I trials in several solid tumors is ongoing (none breast cancer, however). FDA approval for use vs Wilsons disease is pending.