title: The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer.
abstract: Gastric cancer is the second most common cause of cancer-related deaths worldwide. Taxanes have shown therapeutic effects against gastric cancer while also activating the PI3K/mTOR signaling pathway. We investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, alone and in combination with nanoparticle albumin-bound (nab)-paclitaxel in experimental gastric cancer. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. Phosphorylated mTOR and 4E-BP1 levels were elevated in gastric cancer cells and tumor tissues by nab-paclitaxel. BEZ235 effectively inhibited cell proliferation in vitro and provided additive effects in combination with nab-paclitaxel. Furthermore, BEZ235 blocked the activated PI3K/mTOR pathway either alone or in combination with nab-paclitaxel in gastric cancer cells. BEZ235 and nab-paclitaxel caused an increase in PARP-1 and caspase-3 cleavage. Net local tumor growth inhibition for the BEZ235, nab-paclitaxel and BEZ235+nab-paclitaxel groups was 45.1, 77.9 and 97% compared to controls. The effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BEZ235 also caused a decrease in phospho-mTOR and phospho-Akt in tumor tissue lysates. Median animal survival (controls, 23 days) was 26.5 days after BEZ235 (p=0.227), 90.5 days after nab-paclitaxel (p=0.001) and 97 days in the BEZ235+nab-paclitaxel combination treatment group (p=0.001). Our findings suggest that BEZ235 exerts some antitumor effects against gastric cancer and enhances effects of nab-paclitaxel through inhibition of cell proliferation and modulation of the PI3K/mTOR pathway. This approach may represent a promising combination targeted therapy for gastric cancer.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Chang-Ηua
authors.initials: CΗ
authors.lastname: Zhang
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053758:Nanoparticles; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000418:Albumins; D007093:Imidazoles; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; C520255:130-nm albumin-bound paclitaxel; C531198:dactolisib
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