title: A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels.
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.
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. cmstellre@mdanderson.org
authors.forename: Christine M
authors.initials: CM
authors.lastname: Stellrecht
authors.forename: Mary
authors.initials: M
authors.lastname: Ayres
authors.forename: Rishi
authors.initials: R
authors.lastname: Arya
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019927:Cyclin E / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D012313:RNA / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D015762:2-Chloroadenosine; D012313:RNA; C075440:8-chloroadenosine