Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

BMC Cancer. 2020 Nov 3;20(1):1057. doi: 10.1186/s12885-020-07566-x.

Abstract

Background: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined 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 treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using 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.

Keywords: Irradiation; Squamous cell carcinoma of lung; Tumor hypoxia; Tumor necrosis; Vascular disrupting agent; Xenograft model.

MeSH terms

  • Animals
  • Benzophenones / administration & dosage*
  • Benzophenones / pharmacology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Dose Fractionation, Radiation
  • Drug Administration Schedule
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Ki-67 Antigen / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / therapy*
  • Male
  • Mice
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Radiotherapy
  • Treatment Outcome
  • Valine / administration & dosage
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Benzophenones
  • Glucose Transporter Type 1
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ki-67 Antigen
  • MKI67 protein, human
  • N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide
  • Pecam1 protein, mouse
  • Platelet Endothelial Cell Adhesion Molecule-1
  • SLC2A1 protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Valine