Published online May 15, 2023. doi: 10.4251/wjgo.v15.i5.810
Peer-review started: January 3, 2023
First decision: February 13, 2023
Revised: February 17, 2023
Accepted: April 21, 2023
Article in press: April 21, 2023
Published online: May 15, 2023
The growth and spread of colorectal cancer (CRC) are highly dependent on angiogenesis. Epigenetic regulation of the genes in endothelial cells (ECs) in the vicinity of tumor cells plays a vital role in tumor angiogenesis. Sirtuins are class III histone deacetylase enzymes that are implicated in angiogenesis. Their potential roles in cancer have stimulated investigation to seek potent and selective sirtuin (SIRT) inhibitors, potentially leading to new therapeutic breakthroughs. BZD9L1 is a reported small molecule inhibitor with anticancer activities. However, its potential as an anti-angiogenic agent has not been explored.
A patient’s prognosis and survival rate remain heterogenous for which tumor attributes, dynamic host response factors, and treatment quality may be accountable. Some CRC patients become resilient to these anti-angiogenic drugs and standard therapies such as chemotherapy and radiation. Hence, this work opens a new avenue for the establishment of a potential novel anti-angiogenic agent through sirtuin inhibition in tumor angiogenesis.
To determine the anti-angiogenic activity of BZD9L1 benzimidazole analogue in CRC.
The in vitro experiments comprise cell viability, adhesion. spheroid sprouting, quantitative polymerase chain reaction (qPCR), angiogenesis protein array, cell cycle and apoptosis analyses via flow cytometry and indirect co-culture. Mouse choroids were employed to assess the negative impact of BZD9L1 on sprouting and vessel regression. HCT116 CRC cells were injected subcutaneously into athymic nude mice and treated with vehicle control or BZD9L1 at 50 mg/kg and 250 mg/kg. Hematoxylin and eosin staining was performed to determine the percentage of necrosis in the tumor section. Finally, immunohistochemistry and qPCR were conducted to investigate the expression of Ki67 protein and murine CD34/ CD31 as well as SIRT1 and SIRT2, respectively.
Findings from this study highlighted the ability of BZD9L1 to inhibit EC functions in in vitro, ex vivo and co-culture models. Additionally, BZD9L1 retarded tumor growth in vivo compared to the vehicle control group. Overall, the findings underscore the potential of BZD9L1 to treat CRC.
BZD9L1 impeded angiogenesis in ECs, mouse choroid tissues and the CRC xenograft model. This study provides valuable insights into BZD9L1 as a potential anti-angiogenic agent in CRC.
Findings from this study may provide the basis for BZD9L1 benzimidazole analogue as a targeted therapy for the treatment of CRC.