Alhazzani Khalid, Venkatesan Thiagarajan, Natarajan Umamaheswari, Algahtani Mohammad, Alaseem Ali, Alobid Saad, Rathinavelu Appu
Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia.
Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Ave., Fort Lauderdale, FL, 33314, USA.
Biotechnol Lett. 2022 Jun;44(5-6):787-801. doi: 10.1007/s10529-022-03243-0. Epub 2022 Apr 30.
Colorectal cancer (CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation, and/or targeted therapy, which show significant improvement in overall survival. Among the various available treatments, antagonizing VEGF/VEGFR-2 pathways have shown effectiveness in limiting colorectal cancer growth and improving clinical outcomes. In this regard, we hypothesized that F16, a novel VEGFR-2 inhibitor, would control colorectal cancer growth by blocking the VEGFR-2 singling pathway in both in vitro and in vivo conditions. Therefore, the current study was aimed to analyze the efficacy of F16 on the growth of Colo 320DM cells under in vitro and in vivo conditions.
Human RT profiler PCR array analysis results clearly showed that angiogenesis and anti-apoptosis-related gene expressions were significantly reduced in HUVEC cells after F16 (5 μM) treatment. In addition, Western blot results revealed that F16 attenuated the downstream signaling of the VEGFR-2 pathway in HUVEC cells by up-regulating the p53 and p21 levels and down-regulating the p-AKT and p-FAK levels. Accordingly, F16 confirmed potent cytotoxic effects against the cell viability of Colo 320DM tumors, with an IC value of 9.52 ± 1.49 µM. Furthermore, treatment of mice implanted with Colo 320DM xenograft tumors showed a significant reduction in tumor growth and increases in survival rate compared to controls. Immunohistochemistry analysis of tumor tissues showed a reduction in CD31 levels also in F16 treated groups.
These results justify further evaluation of F16 as a potential new therapeutic agent for treating colorectal cancers.
结直肠癌（CRC）是美国第三大常见癌症类型。癌症的治疗选择包括手术、化疗、放疗和/或靶向治疗，这些治疗在总体生存率方面有显著改善。在各种可用治疗方法中，拮抗VEGF/VEGFR - 2通路已显示出在限制结直肠癌生长和改善临床结果方面的有效性。在这方面，我们假设新型VEGFR - 2抑制剂F16在体外和体内条件下通过阻断VEGFR - 2信号通路来控制结直肠癌的生长。因此，本研究旨在分析F16在体外和体内条件下对Colo 320DM细胞生长的疗效。
人RT Profiler PCR阵列分析结果清楚地表明，F16（5 μM）处理后，HUVEC细胞中血管生成和抗凋亡相关基因的表达显著降低。此外，蛋白质印迹结果显示，F16通过上调p53和p21水平以及下调p - AKT和p - FAK水平来减弱HUVEC细胞中VEGFR - 2通路的下游信号传导。相应地，F16对Colo 320DM肿瘤细胞活力具有显著的细胞毒性作用，IC值为9.52±1.49 μM。此外，与对照组相比，对植入Colo 320DM异种移植肿瘤的小鼠进行治疗显示肿瘤生长显著减少且存活率增加。肿瘤组织的免疫组织化学分析表明，F16治疗组的CD31水平也降低。
这些结果证明有必要进一步评估F16作为治疗结直肠癌的潜在新型治疗药物。
