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: Chang-Ηua Zhang, Niranjan Awasthi, Margaret A Schwarz, Roderich E Schwarz
• Journal: International journal of oncology (Int J Oncol) Vol. 43 Issue 5 Pg. 1627-35 (Nov 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24042258 (Publication Type: Journal Article)

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• Proto-Oncogene Proteins c-akt
• Paclitaxel
• dactolisib

Topics

• Albumins (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Synergism
• Female
• Humans
• Imidazoles (pharmacology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Nanoparticles
• Paclitaxel (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Quinolines (pharmacology)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured