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

Title
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
Author(s)
김정애따파디네쉬강유라박필훈노석균이용록한성수구세광[구세광]정연진[정연진]
Keywords
ENDOTHELIAL-GROWTH-FACTOR; CANCER-THERAPY; FACTOR 1-ALPHA; CELL-PROLIFERATION; ANTICANCER AGENTS; DRUG DISCOVERY; BREAST-CANCER; ANGIOGENESIS; CANNABINOIDS; EXPRESSION
Issue Date
201206
Publisher
PHARMACEUTICAL SOC JAPAN
Citation
BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.35, no.6, pp.924 - 932
Abstract
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.
URI
http://hdl.handle.net/YU.REPOSITORY/28149
ISSN
0918-6158
Appears in Collections:
약학대학 > 약학부 > Articles
총장실 > 총장실 > Articles
공과대학 > 화학공학부 > Articles
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