RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia.
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 nonapoptotic 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.
Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
Roman
R
Crazzolara
Kenneth F
KF
Bradstock
Linda J
LJ
Bendall
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D000068338:Everolimus; D006801:Humans; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects
D000068338:Everolimus; D020123:Sirolimus