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Inhibition of Telomerase Activity Enhances Hyperthermia-Mediated Radiosensitization

¹ Department of Radiation Oncology, Washington University School of Medicine; ² Department of Chemistry, Washington University, St. Louis, Missouri; and ³ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Tej K. Pandita, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108. Phone: 314-747-5461; Fax: 314-362-9790; E-mail: pandita{at}wustl.edu.

Key Words: telomerase • heat shock • survival • ionizing radiation • hTR • antisense • LNA • PNA • GRN163L

Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR); however, hyperthermia also induces heat shock protein 70 (HSP70) synthesis and HSP70 expression is associated with radioresistance. Because HSP70 interacts with the telomerase complex and expression of the telomerase catalytic unit (hTERT) extends the life span of the human cells, we determined if heat shock influences telomerase activity and whether telomerase inhibition enhances heat-mediated IR-induced cell killing. In the present study, we show that moderate hyperthermia (43°C) enhances telomerase activity. Inhibition of telomerase activity with human telomerase RNA–targeted antisense agents, and in particular GRN163L, results in enhanced hyperthermia-mediated IR-induced cell killing, and ectopic expression of catalytic unit of telomerase (TERT) decreased hyperthermia-mediated IR-induced cell killing. The increased cell killing by heat and IR exposure in telomerase-inhibited cells correlates with delayed appearance and disappearance of -H2AX foci as well as decreased chromosome repair. These results suggest that inactivation of telomerase before combined hyperthermia and radiotherapy could improve tumor killing. [Cancer Res 2008;68(9):3370–9]