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Induction of p53-independent apoptosis by a novel synthetic hexahydrocannabinol analog is mediated via Sp1-dependent NSAID-activated gene-1 in colon cancer cells

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Author(s)
Dinesh ThapaDinesh BabuMin-A. ParkMi-Kyoung KwakYong-Rok LeeJeong Min KimTaeg Kyu KwonJung-Ae Kim
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Biochemical Pharmacology
Issued Date
2010
Volume
80
Issue
1
Abstract
Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) has received greater attention
as a novel molecular target for anti-cancer therapeutics in recent years. We identified a novel synthetic
hexahydrocannabinol analog, LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-
6H-benzo[c]chromen-2-yl)ethanone)], as a potent NAG-1 and apoptosis inducer in a panel of human
cancer cells. LYR-8 did not possess any affinity for cannabinoid receptor CB1 or CB2,which eliminates the
concern about potential psychoactive side effects. LYR-8 dramatically induced NAG-1 expression and
apoptosis in HCT116 (wild-type p53) and HT29 (mutant p53) colon cancer cells. The NAG-1 expression
by LYR-8 was not blocked by pifithrin-a, a specific p53 inhibitor, which was different from doxorubicin
that induced p53-dependent NAG-1 transcriptional activity. The induction of NAG-1 promoter activity
by LYR-8 was strongly correlated with increased Sp1 activation as noted in various luc-promoter
activities. Furthermore, pretreatment with the specific Sp1 inhibitormithramycin A completely reversed
the LYR-8-induced NAG-1 expression in both HCT116 and HT29 cells. Knockdown of NAG-1 using siRNA
significantly reversed LYR-8-induced cell death in both wild-type and mutant p53-expressing colon
cancer cells. Furthermore, sensitization with NAG-1 inducer sulindac sulfide synergized LYR-8-induced
cell death in both colon cancer cells. These results suggest that induction of NAG-1 via Sp1 activation is a
promising therapeutic approach in cancer treatment, and that a novel compound like LYR-8 could be a
potent chemotherapeutic agent for colon cancers including p53-mutated cancer.
2010 Elsevier Inc. All rights reserved
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine
Citation
Dinesh Thapa et al. (2010). Induction of p53-independent apoptosis by a novel synthetic
hexahydrocannabinol analog is mediated via Sp1-dependent NSAID-activated
gene-1 in colon cancer cells. Biochemical Pharmacology, 80(1), 62–71. doi: 10.1016/j.bcp.2010.03.008
Type
Article
ISSN
0006-2952
Source
https://www.sciencedirect.com/science/article/pii/S0006295210001735?via%3Dihub
DOI
10.1016/j.bcp.2010.03.008
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33700
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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