Anti cancer cells & how Arsenic and Interferon work

[Guest guest]

June 27, 2009 Possible anti- cancer stem cell effects of well known drugs

" 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 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.

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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 s 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. 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. " (We have

discussed this in the past about how patients on INF were more or less

" protected " in some way and some quiescent cells who broke lose and were the

cause of relapse.)

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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.

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citations:

Emmanuelle Passegué & 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.

http://tinyurl.com/2egmfq2

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FYI,

Lottie Duthu