Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma
Abstract Background: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small-cell lung cancer (NSCLC) patients. Vascular disrupting agents (VDAs) mainly affect blood vessels located in the central area of the tumor and lead to a rapid decrease in blood, resulting in massive apoptotic tumor cell death. Thus, we evaluate the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examine tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study.Methods: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After the treatment, tumor tissues were stained with hematoxylin and eosin and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated by immunohistochemical staining.Results: Short-term treatment with IR alone and CKD-516+IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516+IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516+IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516+IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516+IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046).Conclusions: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.