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Autophagic Punctum

RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia

Roman Crazzolara, Kenneth F. Bradstock and Linda J. Bendall

The elimination of tumor cells by apoptosis is the main mechanism of action of chemotherapeutic drugs used in current treatment protocols of acute lymphoblastic leukemia (ALL). Despite the rapid cytoreduction achieved, serious acute and late complications are frequent, and resistance to chemotherapy develops. During the past decade, new strategies to kill cancer cells by non-apoptotic mechanisms have flourished and many mediators of alternate cell death pathways have been identified. In the present study we have evaluated the efficacy of an mTOR inhibitor, RAD001 (Everolimus), to induce autophagy in an in vivo model of childhood ALL. In particular we found that RAD001 increased Beclin 1 expression, the conversion of the soluble form of microtubule-associated protein 1 light chain 3 (LC3) to the autophagic vesicle-associated form LC3-II and the occurence of lysosomes/autophagosomes. Focal degradation of cytoplasmic areas sequestered by autophagic structures was demonstrated by electron microscopy. This effect was associated with massive reduction of leukemic mass and a strong survival advantage for mice treated with RAD001. The discovery of alternative pathways involved in cell death execution and the role that it plays in leukemia suggest mTOR inhibitors should be included in future chemotherapy protocols of ALL.

Punctum to: Crazzolara R, Cisterne A, Thien M, et al. Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 2009; In press.

Authors

Roman Crazzolara

Department of Pediatrics; Medical University of Innsbruck; Innsbruck, Austria

Kenneth F. Bradstock

Department of Haematology; Westmead Hospital; Westmead, NSW, Australia

Linda J. Bendall Corresponding author: linda_bendall@wmi.usyd.edu.au

Westmead Institute for Cancer Research; Westmead Millennium; University of Sydney; Westmead, NSW, Australia