The Drug That’s Getting a Second Chance: Thioridazine and Cancer Stem Cells

Posted on June 25, 2012 by

6


Even when still available, Thioridazine was anything but a first-line drug in treating psychosis or schizophrenia–and that was before it was withdrawn from the market.

In the class of the first-generation or ‘typical’ antipsychotics, its main purpose was to treat the symptoms of schizophrenia–but the National Institute of Health felt it was dangerous enough that they asserted it should only be used with people who had been treated with at least two other medications, with no results, or had experienced severe side effects with the other choices.

Even after the NIH’s restrictions, things went poorly. Known in the U.S. as Mellaril, it eventually was determined that its adverse side effect profile, including risk of cardiac arrhythmias, and, even according to its manufacturers, “sudden death,” was so severe that its manufacturer, Novartis, discontinued the drug worldwide in 2005.

*******************************************************************************

“Everybody deserves a second chance in this world.”

Thus went American actress Shannen Doherty’s philosophy. I’m not sure I’ve totally bought into her belief, but in this case the essence of it applies to medicines.

Think no further than thalidomide, used to treat nausea in pregnant women. The birth defects it caused in the fetus still haunt the public psyche. It seemed the drug could never be redeemed.

And today we use it to treat cancer, multiple myeloma, to be specific, with good results. It is a rehabilitated drug. And the possibilities researchers see for it couldn’t come at a better time.

The Cancer Prevention Coalition claims that overall five-year survival rates for all cancers have remained virtually static since 1970, from 49 to 54%, and incidences of a number of cancers are up. Lung cancer is up 30%, liver cancer 104%, brain cancer 50%–and, more relevant here, acute myeloid leukemia has increased 16%.

More and more scientists believe cure rates will improve by treating the rare and chemotherapy-resistant cancer stem cells.

Cancer stem cells exist within tumors and can replicate and turn into all types of cancer cells. But unlike normal stem cells, they don’t change into stable, non-dividing cell types. It’s a difficult situation, and much treatment has focused on wiping out the cancer cells–along with whatever else is around it–in an effort to stop the progression of the illness.

 Re-enter the formerly discredited thioridazine.
Thioridazine, like many psychotropic medications, targets the brain’s dopamine receptors. And, sure enough, leukemia stem cells express a dopamine receptor on their surface (as do breast cancer stem cells, in fact)-something no self-respecting normal blood stem cell would consider. In the lab, thioridazine located these cells.

That ability to locate the expressed dopamine receptors is a cause for hope. Scientists could use these dopamine receptors as a biomarker, thus allowing early detection and treatment of breast cancer and leukemia.

And although the drug does not kill the cancer stem cells, according to Medical News Today ,it

encourages them to differentiate and therefore exhausts the number of self-renewing cells.

And–better yet– unlike chemo and radiation, it seems to have no effects on non-cancerous cells at all.

Antipsychotic drug treats cancer – Graphical Abstract. Pic courtesy: http://www.cell.com/abstract/S0092-8674(12)00571-5?switch=standard

Now this all seemed pretty promising–and pretty clear, really–as I read the reviews of the research. But I felt put in my place by the actual article, which seemed to have been written for a competition in abstruseness, and required me to re-read each line several times until I could interpret it into usable language. We do owe it to the authors to make some of their own words heard, though. Just hang on through the rough patches. The researchers summarize their fundings thus

. . . assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. [So far so good, if you can get over 'neoplastic' and 'pluripotent,' not words in everyone's daily vocabulary-and the next part is smooth-sailing:] Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. [And then we come to crescendo of acronym-abounding utterance:]  These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs [you with me here? We all together on those neoplastic hPSCs?], and provide support for the use of differentiation as a therapeutic strategy.

Well, having given the authors their due, we’re ready to address the final issue and close:

What now?

Bhatia and his team want the drugs available for patients use as soon as possible. So they’re ready for the next step, which is actual clinical trials, to be conducted on patients with acute myeloid leukemia who have relapsed after chemotherapy. The trials have already been designed.

Bhatia hopes to be able to put their cancer in to remission, and, more so, by targeting those cancer stem cells, actually prevent the cancer from coming back.

The drug that had to leave the schizophrenia-treatment theater, tail between its legs, may yet have a triumphant return in the world of cancer treatment. And not a moment too soon.