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

• Published in: BMC cancer Vol. 20; no. 1; pp. 1057 - 14
• Main Authors: Kim, Min-Young, Shin, Jung-Young, Kim, Jeong-Oh, Son, Kyoung-Hwa, Kim, Yeon Sil, Jung, Chan Kwon, Kang, Jin-Hyoung
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.11.2020; BioMed Central; BMC
• Subjects: Angiogenesis; Animals; Antineoplastic agents; Benzophenones - administration & dosage; Benzophenones - pharmacology; Blood vessels; Cancer therapies; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - therapy; Care and treatment; Cell death; Cell Line, Tumor; Cytoskeleton; Development and progression; Dose Fractionation, Radiation; Drug Administration Schedule; Drug dosages; Experiments; FDA approval; Flavonoids; Gene Expression Regulation, Neoplastic - drug effects; Glucose Transporter Type 1 - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; I.R. radiation; Irradiation; Ki-67 Antigen - metabolism; Laboratory animals; Lung cancer; Lung carcinoma; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Lung tumors; Male; Medical prognosis; Metastasis; Methods; Mice; Necrosis; Non-small cell lung carcinoma; Patient outcomes; Permeability; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Polymerization; Radiation therapy; Radiotherapy; Small cell lung carcinoma; Squamous cell carcinoma; Squamous cell carcinoma of lung; Treatment Outcome; Tubulin; Tumor hypoxia; Tumor necrosis; Tumor necrosis factor-TNF; Tumors; Valine - administration & dosage; Valine - analogs & derivatives; Valine - pharmacology; Vascular disrupting agent; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Xenograft model; Xenografts; South Korea; United States > US; Germany; Irradiation; Tumor hypoxia; Squamous cell carcinoma of lung; Tumor necrosis; Vascular disrupting agent; Xenograft model
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-020-07566-x

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. 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. 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). 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.