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Phosphatidylinositol 3-Kinase Inhibition by LY294002 Radiosensitizes Human Cervical Cancer Cell Lines

Authors' Affiliations: ¹ Department of Radiation Oncology, University of Utah School of Medicine and Huntsman Cancer Hospital; ² Department of Obstetrics and Gynecology, Division of Gynecologic Oncology; and ³ Department of Pathology, Division of Cellular Biology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah; and ⁴ Department of Statistics, Brigham Young University, Provo, Utah

Requests for reprints: Karen A. Zempolich, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah School of Medicine, 30 North 1900 East, Suite 2B200, Salt Lake City, UT 84132. Phone: 801-585-0640; Fax: 801-585-5146; E-mail: karen.zempolich{at}hsc.utah.edu.

Purpose: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki).

Experimental Design: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 µmol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnett's t Test. Microarray gene expression analysis was done on the HeLa cell line.

Results: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P < 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression.

Conclusions: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix.

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