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Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy.

The ability of immobilized lipase from Candida antarctica (Novozym 435) to catalyze the alcoholysis of canola oil and methanol was investigated. Response surface methodology (RSM) and five-level-five-factor central composite rotatable design (CCRD) were employed to evaluate the effects of synthesis parameters, such as reaction time, temperature, enzyme concentration, substrate molar ratio of methanol to canola oil, and added water content on percentage weight conversion of canola oil methyl ester by alcoholysis. Reaction temperature and enzyme concentration were the most important variables. High temperature and superabundant methanol inhibited the ability of Novozym 435 to catalyze the synthesis of biodiesel. Based on the analysis of ridge max, the optimum synthesis conditions were as follows: reaction time 12.4 h, temperature 38.0• C, enzyme concentration 42.3%, substrate molar ratio 3.5:1, and added water 7.2%. The predicted value was 99.4% weight conversion, and the actual experimental value was 97.9% weight conversion.

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