title: The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells.
abstract: Mantle cell lymphoma (MCL) is one of the most difficult B-cell lymphomas to be treated. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is constitutively activated in MCL and plays a critical role in tumor growth and survival. However, single targeted agent mTOR has limited efficacy in treating MCL. Here, we investigate for the first time potential efficacy of NVP-BEZ235 (BEZ235) in treating MCL by simultaneously targeting Akt and mTOR. In this study, phosphorylated Akt and mTOR level were elevated in tissue samples from MCL patients and in MCL cell lines. We also generated bortezomib-resistant MCL cell lines and found increased phosphorylation of Akt and mTOR. Individual inhibition of PI3K or mTOR had limited anti-proliferative effects, whereas dual inhibition with BEZ235 effectively inhibited cell growth. The effect of BEZ235 was synergistic and sensitized the cells to the cytotoxic effects of conventional agents. Furthermore, BEZ235 could overcome acquired resistance to bortezomib in MCL cells and suppress the activated Akt/mTOR pathway. Therefore, these data suggest that the Akt/mTOR pathway plays a key role in the growth and survival of MCL cells and that these proteins may need to be simultaneously targeted for effective treatment of the disease. Our findings suggest that BEZ235 may be an effective agent for the treatment of MCL.
authors.affiliation: Laboratory of Experimental Pathology, Korea Institute of Radiological & Medical Science, Seoul, Republic of Korea.
authors.forename: Areumnuri
authors.initials: A
authors.lastname: Kim
authors.forename: Sunhoo
authors.initials: S
authors.lastname: Park
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Won-Suk
authors.initials: WS
authors.lastname: Jang
authors.forename: Sun-Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Seung-Sook
authors.initials: SS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011804:Quinolines; D000069286:Bortezomib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib