Anti-tumor Activity of the Novel Hexahydrocannabinol Analog LYR-8 in Human Colorectal Tumor Xenograft Is Mediated through the Inhibition of Akt and Hypoxia-Inducible Factor-1 alpha Activation
- Anti-tumor Activity of the Novel Hexahydrocannabinol Analog LYR-8 in Human Colorectal Tumor Xenograft Is Mediated through the Inhibition of Akt and Hypoxia-Inducible Factor-1 alpha Activation
- 김정애; 따파디네쉬; 강유라; 박필훈; 노석균; 이용록; 한성수; 구세광[구세광]; 정연진[정연진]
- ENDOTHELIAL-GROWTH-FACTOR; CANCER-THERAPY; FACTOR 1-ALPHA; CELL-PROLIFERATION; ANTICANCER AGENTS; DRUG DISCOVERY; BREAST-CANCER; ANGIOGENESIS; CANNABINOIDS; EXPRESSION
- Issue Date
- PHARMACEUTICAL SOC JAPAN
- BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.35, no.6, pp.924 - 932
- Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, a novel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl2), LYR-8 dose-dependently suppressed the induction of HIF-1 alpha and subsequently its targets, VEGF and COX-2. in addition, highly elevated prostaglandin E-2 (PGE(2)) concentrations in CoCl2-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl2 did not alter the basal expression of VEGF and COX-2, or PGE(2) production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl2-induced HIF-1 alpha accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1 alpha activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as an anti-tumor agent with a HIF-1 alpha inhibitory activity.
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