Perillyl alcohol as a radio-/chemosensitizer in malignant glioma.
The prognosis for patients with malignant glioma has not significantly changed in two decades, despite advances in surgery, radiation, and chemotherapy, emphasizing the growing need for novel approaches to glioma therapy. Perillyl alcohol (POH) is a naturally occurring monoterpene that has been shown to possess chemotherapeutic as well as chemopreventive activity in animal tumor models and is currently in Phase I and Phase II clinical trials. In the present study, we have demonstrated that POH is an effective radiosensitizer at clinically relevant doses of radiation using established glioma cell lines. POH caused a transient arrest in the G2/M phase of the cell cycle and induced apoptosis in glioma cells. POH treatment sensitized glioma cells to Fas-mediated apoptosis, which was further augmented in the presence of ionizing radiation and abrogated in the presence of antagonistic antibody. POH-induced radiosensitization was partially inhibited in glioma cells expressing dominant negative Fas-associated death domain and completely inhibited in glioma cells overexpressing the cytokine response modifier A. In addition, POH treatment resulted in a dose-dependent sensitization to cisplatin and doxorubicin induced cytotoxicity in glioma cells, highlighting its usefulness as a potent radio/chemosensitizer in the treatment of malignant glioma.
Rajesh
Deepika
D
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA.
Stenzel
Rachelle A
RA
Howard
Steven P
SP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000494:pharmacology; D053222:Fas Ligand Protein; D016195:G2 Phase; D005799:Genes, Dominant; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008938:Mitosis; D039821:Monoterpenes / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D039821:Monoterpenes; D011838:Radiation-Sensitizing Agents; D019014:fas Receptor; C032208:perillyl alcohol; D004317:Doxorubicin; D001973:Bromodeoxyuridine; D002945:Cisplatin