Effect of Rapamycin on the Radio-Sensitivity of Cultured Tumor Cells Following Boron Neutron Capture Reaction

Background: Mammalian target of rapamycin (mTOR) signaling pathway has been implicated in multiple mechanisms of resistance to anticancer drugs and poor treatment outcomes in various human cancers. Meanwhile, clinical boron neutron capture therapy (BNCT) has been carried out for patients with malignant gliomas, melanomas, inoperable head and neck tumors and oral cancers. This study aimed to evaluate the effect of mTOR inhibition on radio-sensitivity of cultured tumor cells in BNCT, employing p-boronophenylalanine-B-10 (BPA) as a B-10-carrier. Methods: Cultured SAS cells had been incubated for 48 h at RPMI medium with mTOR inhibitor, rapamycin at the dose of 1 mu M, and then continuously incubated for 2 more hours at RPMI medium containing both BPA at the B-10 concentration of 10 ppm and rapamycin (1 mu M). Subsequently, the SAS cells received reactor neutron beams, and then surviving fraction and micronucleus frequency were determined. Results: SAS cells incubated with rapamycin showed resistance to gamma-rays compared with no treatment with rapamycin. The efficiency of delivery of B-10 from BPA into cultured SAS cells was reduced through combining with rapamycin, leading to reduced sensitivity following boron neutron capture reaction. Conclusions: Since many tumors are characterized by deregulated PI3K/AKT/mTOR pathway, rapamycin is thought to inhibit the pathway and tumor growth. However, it was revealed that rapamycin can also inhibit the transport of B-10 for BNCT into tumor cells. When BNCT is combined with mTOR inhibitor, the efficiency as cancer treatment can be reduced by repression of distributing B-10 in tumor cells, warranting precaution when the two strategies are combined.