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. 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.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…While the tumor center may necrose, the rim often repopulates rapidly. As such, several VDAs have been tested in combination with additional therapies [ 11 , 41 ], including radiotherapy [ 41 , 42 , 43 , 44 , 45 , 46 ], antiangiogenic agents (such as bevacizumab) [ 47 , 48 ], traditional cytotoxic chemotherapy (e.g., carboplatin, paclitaxel) [ 41 , 49 , 50 , 51 , 52 , 53 , 54 ] and recently immunotherapy [ 55 , 56 ]. There is a current resurgence of interest in VDAs and frequent reports describe novel agents, many based on the colchicine/combretastatin motif [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] ( Figure 2 A).…”

In Vitro and In Vivo Evaluation of a Cyclic LyP-1-Modified Nanosystem for Targeted Endostatin Delivery in a KYSE-30 Cell Xenograft Athymic Nude Mice Model

“…In essence, an increase in tumor size should account for a reduced total body weight due to weight loss from cancer cachexia [ 56 , 57 , 58 ]. As such, the control group with a high tumor volume displayed a reduced total body weight (29.20–22.96 g) compared with the treated group ( Figure 11 ) ( p < 0.05).…”

“…More importantly, the ENT-loaded LyP-1-modified nanosystem provided targeted drug delivery with superior anti-tumor effects of ENT to potentially treat OSCC. In essence, an increase in tumor size should account for a reduced total body weight due to weight loss from cancer cachexia [56][57][58]. As such, the control group with a high tumor volume displayed a reduced total body weight (29.20-22.96 g) compared with the treated group (Figure 11) (p < 0.05).…”

TME-Related Biomimetic Strategies Against Cancer

“…41 Blood vessels in tumors are also structurally different from those in normal tissues. 42 ECs are neatly arranged in normal tissues, where pericytes (PCs) are closely bonded to ECs. 43,44 Vascular-targeted therapy strategies are mainly focused on inhibiting key signaling pathways that promote tumor angiogenesis, down-regulate the expression of vasoactive factors, inhibit tumor angiogenesis, cut off tumor feeding, and curb tumor growth, recurrence and metastasis 45,46 (Table 1).…”

“…Blood vessels in tumors are also structurally different from those in normal tissues. 42 ECs are neatly arranged in normal tissues, where pericytes (PCs) are closely bonded to ECs. 43 , 44 …”