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Chemotherapy Induces Tumor Clearance Independent of Apoptosis

¹ Graduate Program in Molecular and Cellular Biology, Departments of ² Molecular Genetics and Microbiology and ³ Pharmacological Sciences, Stony Brook University, Stony Brook, New York; and ⁴ Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Wei-Xing Zong, 218 Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5222. Phone: 631-632-4104; Fax: 631-632-9797; E-mail: wzong{at}notes.cc.sunysb.edu.

Key Words: chemotherapy • apoptosis • necrosis • Bcl-2 • innate immunity

Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. The ultimate goal of cancer treatment is to selectively induce cancer cell death and overcome drug resistance. A deeper understanding of how a given chemotherapy affects tumor cell death is needed to develop strategically designed anticancer agents. Here, we use a xenograft mouse tumor system generated from genetically defined cells deficient in apoptosis to examine the involvement of multiple forms of cell death induced by cyclophosphamide (CP), a DNA alkylating agent commonly used in chemotherapy. We find that although apoptosis facilitates tumor regression, it is dispensable for complete tumor regression as other forms of cell death are activated. Sporadic necrosis is observed in both apoptosis-competent and deficient tumors evident by tumor cell morphology, extracellular release of high mobility group box 1 protein, and activation of innate immune cells in CP-treated tumors. Our findings indicate that in apoptosis-deficient tumors, necrosis may play a fundamental role in tumor clearance by stimulating the innate immune response. [Cancer Res 2008;68(23):9595–600]