Tuesday, June 5, 2012

I'm not crazy: Thioridazine really does target cancer stem cells

Research has shown that the drug, Thioridazine, an antipsychotic drug normally used to treat Schizophrenia, may also be used as a targeted treatment for cancer.  While Thioridazine killed a precursor to leukemia cells, it did not harm the normal cells – the ultimate goal with all cancer treatment.  By targeting only the leukemia cells, thioridazine has the potential to permanently eradicate them, such that a secondary tumor never forms.

Surgery, along with chemotherapy, and radiation are part of the standard western regime for cancer treatment.  While this trio is usually the initial treatment for most, if not all cancers, often they are too invasive, have minimal efficacy, and are equipped with numerous side-effects. More importantly, these cytotoxic treatments are a temporary solution – within years, or in some cases months, the cancer cells have returned, usually with a faster proliferation rate, making them nearly untreatable.  These cancer cells, that resist radio and chemotherapies, can most likely all be classified as cancer stems cells (CSCs).

Combining conventional cancer treatment, with drugs that target CSCs, like Thioridazine, researchers believe, is the most potent anti-cancer solution.

Problem: CSCs are rare and difficult to grow in vitro; therefore, only a few drugs that have the ability to target CSCs have been identified and are in clinical trial only, not yet in clinical use.

But wait – might there be a solution?

Perhaps an innovative one that tests for such CSC-targeting drugs?

Indeed! - A Canadian team has recently discovered a novel way to test for drugs that can potentially target CSCs.

What did they do, you ask?

Why, they used human pluripotent stem cells! Pluripotent stem cells are formed from embryos. However, they can also be formed by reprogramming adult stem cells to differentiate into various types of tissues. This discovery was made only a few years ago, when researchers in Canada came across pluripotent stem cell lines that coincidentally possessed similar characteristics of CSCs. Amongst the stem cell lines, they observed either abnormal dividing or differentiation into specialized cells.

The test: Determine if different chemical compounds could induce differentiation or maturation into normal adult cells.

Their discovery: Thioridazine -It induced differentiation in CSCs and did not affect the normal stem cells.

Figure: CSCs treated with Thioridazine (right) are scarce compared with the control.

That’s not all…

Thioridazine also inhibited acute myeloid leukemia (AML) stem cell growth in samples taken from various (human) patients.

Other promising and striking discoveries:

  • Thioridazine, combined with the standard AML medicine, had a 55x greater efficacy, in comparison to treating with the standard drug alone. This result supports the idea that drug "cocktails" have the highest success rate.
  •  Thioridazine is normally used to treat Schizophrenia by blocking dopamine receptors; oddly enough, leukemia stem cells express the same dopamine receptors, in which Thioridazine effectively blocks as well.
Thioridazine appears to be a promising drug for targeted CSC treatment. The fact that it inhibited AML stem cell growth in human tissue is an encouraging representation of its effects in vivo. However, being that this drug was only discovered a few years ago, its side-effects cannot be assessed, which can be potentially dangerous for any patient who is treated with it while it’s still in clinical trial.  Regardless, the discoveries made with Thioridazine thus far make the drug’s future seem very reassuring.