A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels.

Breast Cancer Res Treat 2010 Jun 30;121(2):355-64. Epub 2009 Jul 30.

Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

In contrast to deoxyribose or arabinose containing nucleoside analogs that are currently established for cancer therapeutics, 8-chloro-adenosine (8-Cl-Ado) possesses a ribose sugar. This unique nucleoside analog is RNA-directed and is in a phase I clinical trial for hematological malignancies. RNA-directed therapies are effective for the treatment of many malignancies as their activities are primarily aimed at short-lived transcripts, which are typically encoded by genes that promote the growth and survival of tumor cells such as cyclin E in breast cancer. Based on this, we hypothesized that 8-Cl-Ado, a transcription inhibitor, will be effective for the treatment of breast cancer cells. The metabolism of 8-Cl-Ado and the effect on ATP in the breast cancer cell lines MCF-7 and BT-474 were measured using HPLC analysis. In these cells, 8-Cl-Ado was effectively taken up, converted to its cytotoxic metabolite, 8-Cl-ATP, and depleted the endogenous ATP levels. This in turn led to an inhibition of RNA synthesis. The RNA synthesis inhibition was associated with a depletion of cyclin E expression, which is indicative of a diminished tumorigenic phenotype. The final outcome of 8-Cl-Ado treatment of the breast cancer cells was growth inhibition due to an induction of apoptosis and a loss of clonogenic survival. These results indicate that 8-Cl-Ado, which is currently in clinic for hematological malignancies, may be an effective agent for the treatment of breast cancer.

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http://link.springer.com/10.1007/s10549-009-0481-3
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http://dx.doi.org/10.1007/s10549-009-0481-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739050PMC
June 2010
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