Abstract
Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.
Highlights
Colorectal cancer (CRC) is one among the major malignant tumors having a high rate of incidence and mortality, nearly about two million new cases were diagnosed, and one million deaths were registered in 2018
To investigate the anti-angiogenic activity of BCP in vitro, human umbilical vein endothelial cells (HUVECs) were cultured in 96-well plates and incubated with BCP for 24 h in a concentration range of 6.12 to 100 μM
The migration of vascular endothelial cells represents a crucial step toward the development of new blood vessels, allowing the cells to propagate from pre-existing locations and form a network of new vessels
Summary
Colorectal cancer (CRC) is one among the major malignant tumors having a high rate of incidence and mortality, nearly about two million new cases were diagnosed, and one million deaths were registered in 2018. 77% more new CRC cases in the coming years, resulting in 80% more deaths by 2030 [3] These data reflect that CRC is a severe health problem, requiring further attention to find new anti-cancer agents and gain more insights into better therapeutic results. Medicinal plants and their derivatives have been shown to have promising potential in the fight against human cancer, both in preventing and treating the patients [4]. Natural products can stop or slow down multiple pathways of carcinogenesis [5], for example, angiogenesis and apoptosis, which are the main driving forces in regulating solid tumors’ development
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