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Autophagy: A Novel Mechanism of Synergistic Cytotoxicity between Doxorubicin and Roscovitine in a Sarcoma Model

Departments of ¹ Surgical Oncology, ² Experimental Radiation Oncology, and ³ Systems Biology, University of Texas - M. D. Anderson Cancer Center, Houston, Texas; and ⁴ Protein Phosphorylation and Disease, Centre National de la Recherche Scientifique, Station Biologique, Roscoff, France

Requests for reprints: Khandan Keyomarsi, Department of Experimental Radiation Oncology, Unit 0066, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-4845; Fax: 713-794-5369; E-mail: kkeyomar{at}mdanderson.org.

Key Words: roscovitine • doxorubicin • autophagy • synergy • cell cycle

Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G₂-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted. [Cancer Res 2008;68(19):7966–74]

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