caryophyllene and Colorectal-Neoplasms

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Movement; Cell Proliferation; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Colorectal Neoplasms; HCT116 Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Nude; Microvessels; Neovascularization, Pathologic; Polycyclic Sesquiterpenes; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of the development of colorectal cancer (CRC). A previous study revealed that the levels of arginine-specific mono-ADP-ribosyltransferase 1 (ART1) in CRC tissues from patients with T2DM were higher than in non-diabetic patients. Hyperglycemia, which is a risk factor of cancer, is a common feature of T2DM; however, the effects of ART1 on glycolysis and energy metabolism in CRC cells under high-glucose conditions remains to be elucidated. β-caryophyllene (BCP) has been reported to exert anticancer and hypoglycemic effects. In the present study, CT26 cells were cultured under a high-glucose conditions and the expression levels of relevant factors were detected by western blotting. Cell Counting Kit-8 assay, flow cytometry, Hoechst 33258 staining, ATP assay and lactic acid assay were used to detect the proliferation, apoptosis and energy metabolism of CT26 cells. To observe the effects of ART1 and BCP on tumor growth in vivo, CT26 cell tumors were successfully transplanted into BALB/c mice with T2DM. The results demonstrated that overexpression of ART1 may increase glycolysis and energy metabolism in CT26 CRC cells under high glucose conditions by regulating the protein kinase B/mammalian target of rapamycin/c‑Myc signaling pathway and the expression of glycolytic enzymes. BCP inhibited the effects induced by ART1, which may be due to a BCP-induced reduction in the expression levels of ART1 via nuclear factor-κB. Therefore, ART1 may be considered a therapeutic target for the treatment of diabetic patients with CRC.

Topics: ADP Ribose Transferases; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Glycolysis; GPI-Linked Proteins; Humans; Male; Mice; Mice, Inbred BALB C; Polycyclic Sesquiterpenes; RNA, Small Interfering; Sesquiterpenes; Signal Transduction; Streptozocin; Xenograft Model Antitumor Assays