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-1α activation.

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-1α), 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 (CoCl(2)), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E(2) (PGE(2)) concentrations in CoCl(2)-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl(2) 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 CoCl(2)-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α 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-1α inhibitory activity.

• Authors: Dinesh Thapa, Youra Kang, Pil-Hoon Park, Seok Kyun Noh, Yong Rok Lee, Sung Soo Han, Sae Kwang Ku, Yunjin Jung, Jung-Ae Kim
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 35 Issue 6 Pg. 924-32 ( 2012) ISSN: 1347-5215 [Electronic] Japan
• PMID: 22687485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo(c)chromen-2-yl)ethanone
• Angiogenesis Inhibitors
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Dronabinol
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Proto-Oncogene Proteins c-akt

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Chickens
• Chorioallantoic Membrane
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Cyclooxygenase 2 (metabolism)
• Dronabinol (analogs & derivatives, pharmacology, therapeutic use)
• HT29 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays