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.
Highlights
Gastric cancer (GC) is the fourth most prevalent cancer and the second most common cause of cancer-related deaths throughout the world [1,2,3]
We recently demonstrated that nab-paclitaxel showed stronger antitumor effects in experimental gastric cancer than contemporary commonly used cytotoxic agents such as oxaliplatin, epirubicin and docetaxel (16b)
Combination index (CI) values were
Summary
Gastric cancer (GC) is the fourth most prevalent cancer and the second most common cause of cancer-related deaths throughout the world [1,2,3]. Current combination therapies with oxaliplatin and 5-fluorouracil carry limited efficacy but have the potential for considerable side effects [4,5,6,7]. Clinical and experimental studies demonstrated that compared with solvent-based paclitaxel, nab-paclitaxel had higher tumor retention, lower toxicity [10,11] and more potent antitumor effects on ovarian cancer, melanoma, non-small cell lung carcinoma (NSCLC), breast cancer and pancreatic cancer (12-16a). We recently demonstrated that nab-paclitaxel showed stronger antitumor effects in experimental gastric cancer than contemporary commonly used cytotoxic agents such as oxaliplatin, epirubicin and docetaxel (16b). Delineating the mechanism that restricts response and drives tumor resistance to nabpaclitaxel is important to improve its antitumor efficacy and explore more effective combination therapies
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