In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18F-FDG PET/CT

Abstract

PurposeHypoxia-inducible factor 1α (HIF-1α) and glucose transporter-1 (GLUT-1) are two important hypoxic markers associated with the radioresistance of cancers including laryngeal carcinoma. We evaluated whether the simultaneous inhibition of GLUT-1 and HIF-1α expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1α and GLUT-1 was correlated with 2′-deoxy-2’-[18F]fluoro-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography-computed tomography (PET/CT) was appropriate for early evaluation of the response of laryngeal carcinoma to targeted treatment in vivo.Materials and MethodsTo verify the above hypotheses, an in vivo model was applied by subcutaneously injecting Hep-2 (2 × 107/mL × 0.2 mL) and Tu212 cells (2 × 107/mL × 0.2 mL) into nude mice. The effects of HIF-1α antisense oligodeoxynucleotides (AS-ODNs) (100 μg) and GLUT-1 AS-ODNs (100 μg) on the radiosensitivity of laryngeal carcinoma were assessed by tumor volume and weight, microvessel density (MVD), apoptosis index (AI) and necrosis in vivo based on a full factorial (23) design. 18F-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1α and GLUT-1 expression and 18F-FDG uptake in xenografts were estimated and the value of 18F-FDG-PET/CT was assessed after treating the xenografts.Results10 Gy X-ray irradiation decreased the weight of Hep-2 xenografts 8 and 12 days after treatment, and the weights of Tu212 xenografts 8 days after treatment. GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts 12 days after treatment. There was a synergistic interaction among the three treatments (GLUT-1 AS-ODNs, HIF-1α AS-ODNs and 10Gy X-ray irradiation) in increasing apoptosis, decreasing MVD, and increasing necrosis in Hep-2 xenografts 8 days after treatment (p < 0.05) and in Tu212 xenografts 12 days after treatment (p < 0.001). Standardized uptake value (tumor/normal tissue)( SUVmaxT/N) did not show a statistically significant correlation with GLUT1 and HIF-1α expression and therapeutic effect (necrosis, apoptosis).ConclusionsSimultaneous inhibition of HIF-1α and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. 18F-FDG-PET/CT wasn't useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.

shRNA Glut-1 inhibits cell viability, apoptosis and migration of laryngeal carcinoma HEp-2 cells through regulating Beclin-1-mediated autophagy

“…Glut-1 also affects cell proliferation and chemoradiotherapy sensitivity of head and neck squamous cell carcinoma, including laryngeal carcinoma13-18. Our previous studies suggested that Glut-1 may affect the proliferation, glucose uptake, chemosensitivity, and radiosensitivity [8,[13][14][15][16][17]. Although we found that the mechanism may be mediated through the PI3K/Akt pathway, the role of the activated PI3K/Akt pathway in this process was not significant.…”

Effect of combination of curcumin and GLUT‐1 AS‐ODN on radiosensitivity of laryngeal carcinoma through regulating autophagy

“…42 Inhibition of GLUT-1 may enhance the radiosensitivity of laryngeal carcinomas through decreasing microvessel density and promoting apoptosis and necrosis. 43 Activation of the PI3K/Akt pathway-mediated the trafficking and activity of GLUT-1 is positively associated with radioresistance. 44 In our previous study, we revealed that overexpression of GLUT-1-induced the radioresistance of laryngeal carcinoma was through activating PI3K/Akt pathway.…”

Inhibition of GLUT-1 expression and the PI3K/Akt pathway to enhance the chemosensitivity of laryngeal carcinoma cells in vitro

“…Although promising treatments preserving laryngeal function, including chemotherapy and radiotherapy, have been advanced, the overall survival rate of patients with laryngeal carcinoma remains poor. 1 , 2 One possible mechanism may be the development of chemoradioresistance in laryngeal carcinoma. Studies have demonstrated that hypoxia plays a key role in laryngeal carcinoma radioresistance: 3 – 6 1) Glucose transporter-1 (GLUT-1), as an important hypoxic marker, has also been found to have an important role in laryngeal carcinoma radiosensitivity, and inhibition of GLUT-1 expression may enhance the radiosensitivity of laryngeal carcinoma; 2 , 6 – 9 2) HIF-1α, as another important hypoxic marker, has also been found to have an important role in laryngeal carcinoma radiosensitivity, and inhibition of HIF-1α expression may enhance the radiosensitivity of laryngeal carcinoma.…”