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

Thapa, Dinesh; Babu, Dinesh; Park, Min-A; Kwak, Mi‐Kyoung; Lee, Yong Rok; Kim, Jeong‐Min; Kwon, Taeg Kyu; Kim, Jung-Ae

doi:10.1016/j.bcp.2010.03.008

Cited by 20 publications

(16 citation statements)

References 46 publications

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“…Most in vitro studies related to NAG-1 function in colorectal cancer suggest a tumor suppressor role of NAG-1. For example, many anti-cancer compounds increased NAG-1 expression in colorectal cancer cells [53–55] and tumor suppressor proteins control the NAG-1 expression [56]. Recent data suggests that NAG-1 is a downstream target of ER stress, mediating ER-stress-induced apoptosis [57].…”

Section: Nag-1 and Colorectal Cancermentioning

confidence: 99%

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer

Wang

Baek

Eling

2013

Biochemical Pharmacology

141

155

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Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3β, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-β family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-1 may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression.

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Section: Nag-1 and Colorectal Cancermentioning

confidence: 99%

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer

Wang

Baek

Eling

2013

Biochemical Pharmacology

141

155

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“…For these chemoresistant cancer cases, new approaches that target specifically mutant p53 or restore wild-type TP53 by delivering it by gene therapy have been currently explored (Cheok et al, 2011;Frezza and Martins, 2012). Alternatively, for treatment of p53 mutant tumors that have acquired resistance toward apoptosis, new drugs that sensitize cancer cells to apoptotic death by p53-independent mechanisms should be developed (Lanni et al, 1997;Bai et al, 2004;Thapa et al, 2010;Yerlikaya et al, 2012). The novel compound 2a tested here demonstrated the ability to kill HCT116 cancer cells by a p53-independent mechanism.…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, p53-based therapies are being increasingly exploited by different approaches, such as by using drugs that target specifically mutant p53, that restore wild-type p53 function, and that inhibit MDM2 (HDM2 in humans, an oncogenic E3 ligase) (Cheok et al, 2011;Frezza and Martins, 2012). However, considering that so many tumors possess p53 mutations, the induction of cancer cell death by p53-independent mechanisms provides an alternative strategy (Lanni et al, 1997;Bai et al, 2004;Thapa et al, 2010). Thus, drugs that induce apoptosis independently of p53 signaling may be of great value in cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells

Lima

Costa

Proença

et al. 2015

European Journal of Pharmaceutical Sciences

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“…12,13) We recently synthesized and evaluated the anti-cancer effects of a novel series of hexahydrocannabinol analogs. [14][15][16] Of these analogs, LYR-8, a cannabinoid-like compound with no affinity for conventional cannabinoid receptors (CB 1 and CB 2 ), was found to directly inhibit the growth, induce apoptosis of cancer cells and inhibit endothelial cell proliferation and angiogenesis. In addition, we observed that the apoptotic activity of LYR-8 in colon cancer cells was mediated by p53-independent NAG-1 activation and by the induction of other apoptotic markers such as p21 and caspase-3.…”

mentioning

confidence: 99%

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

Thapa

Kang

Park

et al. 2012

Biological & Pharmaceutical Bulletin

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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.

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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

Cited by 20 publications

References 46 publications

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer

Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells

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

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