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    Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

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    Author
    Iacovelli, Stefano; Ricciardi, Maria Rosaria; Allegretti, Matteo; Mirabilii, Simone; Licchetta, Roberto; Bergamo, Paola; Rinaldo, Cinzia; Zeuner, Ann; Foá , Robin; Milella, Michele; McCubrey, James A.; Martelli, Alberto M.; Tafuri, Agostino
    Abstract
    Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.
    URI
    http://hdl.handle.net/10342/5680
    Subject
     acute lymphoblastic leukemia; targeted therapies; BH3 mimetic resistance; mTOR inhibition; Mcl-1 
    Date
    2015-10
    Citation:
    APA:
    Iacovelli, Stefano, & Ricciardi, Maria Rosaria, & Allegretti, Matteo, & Mirabilii, Simone, & Licchetta, Roberto, & Bergamo, Paola, & Rinaldo, Cinzia, & Zeuner, Ann, & Foá , Robin, & Milella, Michele, & McCubrey, James A., & Martelli, Alberto M., & Tafuri, Agostino. (October 2015). Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. Oncotarget, 6(31), 32089- 32103. Retrieved from http://hdl.handle.net/10342/5680

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    MLA:
    Iacovelli, Stefano, and Ricciardi, Maria Rosaria, and Allegretti, Matteo, and Mirabilii, Simone, and Licchetta, Roberto, and Bergamo, Paola, and Rinaldo, Cinzia, and Zeuner, Ann, and Foá , Robin, and Milella, Michele, and McCubrey, James A., and Martelli, Alberto M., and Tafuri, Agostino. "Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia". Oncotarget. 6:31. (32089-32103), October 2015. December 08, 2023. http://hdl.handle.net/10342/5680.
    Chicago:
    Iacovelli, Stefano and Ricciardi, Maria Rosaria and Allegretti, Matteo and Mirabilii, Simone and Licchetta, Roberto and Bergamo, Paola and Rinaldo, Cinzia and Zeuner, Ann and Foá , Robin and Milella, Michele and McCubrey, James A. and Martelli, Alberto M. and Tafuri, Agostino, "Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia," Oncotarget 6, no. 31 (October 2015), http://hdl.handle.net/10342/5680 (accessed December 08, 2023).
    AMA:
    Iacovelli, Stefano, Ricciardi, Maria Rosaria, Allegretti, Matteo, Mirabilii, Simone, Licchetta, Roberto, Bergamo, Paola, Rinaldo, Cinzia, Zeuner, Ann, Foá , Robin, Milella, Michele, McCubrey, James A., Martelli, Alberto M., Tafuri, Agostino. Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. Oncotarget. October 2015; 6(31): 32089-32103. http://hdl.handle.net/10342/5680. Accessed December 08, 2023.
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