A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia

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Chiarini, Francesca; Lonetti, Annalisa; Teti, Gabriella; Orsini, Ester; Bressanin, Daniela; Cappellini, Alessandra; Ricci, Francesca; Tazzari, Pier Luigi; Ognibene, Andrea; Falconi, Mirella; Pagliaro, Pasqualepaolo; Iacobucci, Ilaria; Martinelli, Giovanni; Amadori, Sergio; McCubrey, James A.; Martelli, Alberto M.
Abstract
Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is aberrantly activated in acute myeloid leukemia (AML) patients, where it contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, inhibiting mTOR signaling in AML blasts could enhance their sensitivity to cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition with rapamycin impaired leukemia initiating cells (LICs) function. In this study, we assessed the therapeutic potential of a combination consisting of temsirolimus [an allosteric mTOR complex 1 (mTORC1) inhibitor] with clofarabine, a nucleoside analogue with potent inhibitory effects on both ribonucleotide reductase and DNA polymerase. The drug combination (CLO-TOR) displayed synergistic cytotoxic effects against a panel of AML cell lines and primary cells from AML patients. Treatment with CLO-TOR induced a G0/G1-phase cell cycle arrest, apoptosis, and autophagy. CLO-TOR was pro-apoptotic in an AML patient blast subset (CD34+/CD38−/CD123+), which is enriched in putative leukemia initiating cells (LICs). In summary, the CLO-TOR combination could represent a novel valuable treatment for AML patients, also in light of its efficacy against LICs.
URI
http://hdl.handle.net/10342/5553
Subject
 AML; PI3K/Akt/mTOR signaling; apoptosis; autophagy; combination therapy; leukemia initiating cells 
Date
2012-12
Citation:
APA:
Chiarini, Francesca, & Lonetti, Annalisa, & Teti, Gabriella, & Orsini, Ester, & Bressanin, Daniela, & Cappellini, Alessandra, & Ricci, Francesca, & Tazzari, Pier Luigi, & Ognibene, Andrea, & Falconi, Mirella, & Pagliaro, Pasqualepaolo, & Iacobucci, Ilaria, & Martinelli, Giovanni, & Amadori, Sergio, & McCubrey, James A., & Martelli, Alberto M.. (December 2012). A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget, 3(12), 1615- 1628. Retrieved from http://hdl.handle.net/10342/5553

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MLA:
Chiarini, Francesca, and Lonetti, Annalisa, and Teti, Gabriella, and Orsini, Ester, and Bressanin, Daniela, and Cappellini, Alessandra, and Ricci, Francesca, and Tazzari, Pier Luigi, and Ognibene, Andrea, and Falconi, Mirella, and Pagliaro, Pasqualepaolo, and Iacobucci, Ilaria, and Martinelli, Giovanni, and Amadori, Sergio, and McCubrey, James A., and Martelli, Alberto M.. "A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia". Oncotarget. 3:12. (1615-1628), December 2012. September 21, 2023. http://hdl.handle.net/10342/5553.
Chicago:
Chiarini, Francesca and Lonetti, Annalisa and Teti, Gabriella and Orsini, Ester and Bressanin, Daniela and Cappellini, Alessandra and Ricci, Francesca and Tazzari, Pier Luigi and Ognibene, Andrea and Falconi, Mirella and Pagliaro, Pasqualepaolo and Iacobucci, Ilaria and Martinelli, Giovanni and Amadori, Sergio and McCubrey, James A. and Martelli, Alberto M., "A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia," Oncotarget 3, no. 12 (December 2012), http://hdl.handle.net/10342/5553 (accessed September 21, 2023).
AMA:
Chiarini, Francesca, Lonetti, Annalisa, Teti, Gabriella, Orsini, Ester, Bressanin, Daniela, Cappellini, Alessandra, Ricci, Francesca, Tazzari, Pier Luigi, Ognibene, Andrea, Falconi, Mirella, Pagliaro, Pasqualepaolo, Iacobucci, Ilaria, Martinelli, Giovanni, Amadori, Sergio, McCubrey, James A., Martelli, Alberto M.. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget. December 2012; 3(12): 1615-1628. http://hdl.handle.net/10342/5553. Accessed September 21, 2023.
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