Paclitaxel pretreatment overcomes hypoxia inducible factor-1α-induced radioresistance acquisition of human hepatoma and lung adenocarcinoma cells

Aims: This study delineated the mechanisms of paclitaxel (PTX) assistance in overcoming radioresistance in hepatoma and human lung adenocarcinoma (HLAC) cells. Main methods: The TUNEL assay was used as an index of radiosensitivity, and the MTT assay assessed the efficacy of various combined PTX/RT treatments. The efficacy of PTX disruptions of hypoxia-inducible factor-1 alpha (HIF-1 alpha) was assessed using Western blotting. Key findings: Normoxically overexpressed HIF-1 alpha in hepatoma J5 cells was mechanistically linked to activation of the bFGF/PI3K/Akt pathway because the viability of these cells was strongly inhibited by either Akt inhibitors or an HIF-1 alpha inhibitor. All of the cell lines used were extremely sensitive to PTX, and these effects also correlated excellently with HIF-1 alpha suppression. We designed five combined radiation-PTX protocols of varying dose duration and treatment sequences against CL1-1 cells based on the gathered data. Pretreatment of CL1-1 cells with PTX (100 nM) for 24 h before irradiation (2.5 Gy) was the best combined protocol to achieve maximum radiosensitizing effects. Significance: Our data clearly indicate that PTX pretreatment is an effective radiosensitizing procedure against HIF-1 alpha-expressing hepatoma and HLAC cells, which are constitutively endowed with radioresistance. (C) 2015 Elsevier Inc. All rights reserved.