Preclinical study

Breast Cancer Research and Treatment

, Volume 121, Issue 2, pp 355-364

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

  • Christine M. StellrechtAffiliated withDepartment of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center Email author 
  • , Mary AyresAffiliated withDepartment of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center
  • , Rishi AryaAffiliated withDepartment of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center
  • , Varsha GandhiAffiliated withDepartment of Experimental Therapeutics, University of Texas M.D. Anderson Cancer CenterDepartment of Leukemia, University of Texas M.D. Anderson Cancer Center

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Abstract

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.

Keywords

8-chloro-adenosine Breast cancer Nucleoside analog RNA synthesis inhibition Cyclin E