Cancer stem cell concept implies identification of selective markers, different from normal cells, which potentially could be targeted by newly designed drugs.
Recently, anti-cancer activity of some well known drugs was discovered, which was shown to rely on targeting of cancer stem cells (CSC). Explanations for some very effective anti-leukemic drug combination were recently found in the laboratories. I’ll give you some examples of “from-bed-to-the-bench” translation coming from leukemia clinic.
Arsenic targets quiescent leukemic stem cell
Ido et al showed that arsenic trioxide specifically targets quiescent leukemia-initiating cells (LIC) in chronic myelogenous leukaemia model. Arsenic trioxide selectively and reversibly decreases PML protein expression on hematopoietic stem cells (HSC) and LIC and causes their impaired quiescence and self-renewal.
Arsenic trioxide-induced cycling increased LIC-killing effect of another anti-leukemic drug – Ara-C, which induces apoptosis of dividing cells. The combination of both drugs was able to inhibit leukemogenesis in secondary BMT unlike Ara-C treatment only. Even more, only by combining these two drugs leads to complete cure (ei LIC eradication) of disease in half of recipient mice.
Authors consider that this mechanism could be a possible explanation of dramatic ability of arsenic to cure acute promyelocytic leukemia (APL). I’d remind you that arsenic has been used for treatment of leukemia for centuries.
Yet another study provides the same explanation for therapeutic efficacy of arsenic with retinoic acid in treatment of APL. These drugs, which successfully have been used in leukemia clinic, acts through degradation of fusion PML-RARA in LIC blocking their self-renewal.
Interferon wakes up dormant hematopoietic stem cells
Two recent studies provided evidences for one possible mechanisms for manipulation of quiescent hematopoietic stem cells (HSC). The first study came from Andreas Trumpp lab and describes how interferon-alpha stimulates HSC proliferation through exit from quiescent state. Sato et al, found that mice, deficient for one of the components of the IFN pathway, have abnormal proliferation of HSC leading to their rapid functional exhaustion.
So far, we don’t know if we can apply this results for targeting quiescent LIC, but it was proposed as possible explanation of IFN efficacy in combinational therapy of CML.
Persistent CML-initiating cells, or CML stem cells, which are protected from imatinib killing by their quiescent status, are probably responsible for the regrowth of the disease.
Strikingly, a handful of CML patients that were first treated with IFN-alpha and then switched to imatinib treatment—a molecularly targeted therapy directed against BCR-ABL, the fusion protein characteristic of CML – experienced persistent remission…
The emerging possibility to explain the stable remission in the patients previously treated with IFN-alpha could be that the exposure to IFN-alpha induced the CML stem cells to exit quiescence and proliferate such that, upon imatinib treatment, they became vulnerable to imatinib rather than remaining protected.
Zileuton selectively targets CML stem cells
Recently, well-known 5-Lipoxygenase inhibitor – Zileuton alone or in combination with Gleevec, was found unexpectedly effective in eradication of LIC. Zileuton is widely used for asthma treatment, where it mechanistically inhibits the Alox5 gene.
The researchers found that CML did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.
Zileuton is not in clinical trial for leukemia treatment yet, but it was proposed in Chen’s study.
This essay is aimed to show how drug-resistance to one agent (Glivec for instance), discovered in leukemia clinic, could lead to investigation in laboratory and possible explanation by cancer stem cell theory. Targeting of leukemia-initiating cells by additional drugs underlies achieving of successful clinical and cytological remission.
Emmanuelle Passegué & Patricia Ernst. IFN-alpha wakes up sleeping hematopoietic stem cells. Nat Med 2009; 15: 612 – 613
A lethal cancer knocked down by one-two drug punch. GEN June 7.