Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: Involvement of the transcription factor PPARγ

Giuliano, Michela; Pellerito, Ornella; Portanova, Patrizia; Calvaruso, Giuseppe; Santulli, Andrea; Blasio, Anna De; Vento, Renza; Tesoriere, Giovanni

doi:10.1016/j.biochi.2008.11.003

Cited by 62 publications

(62 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in line with the recent observation that the synthetic cannabinoid WIN-55, 212-2-induced apoptosis in HepG2 cells in a process that was partially inhibited by the CB 2 receptor-selective antagonist AM630. 11 Moreover, it has been previously shown that CB 2 receptors are overexpressed in HCC and correlate with good prognosis. 31 Those findings, together with ours, support the fact that stimulation of CB 2 receptors could be a new therapeutic strategy to promote HCC death.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Recent research has also reported that the synthetic cannabinoid WIN-55 212-2 inhibits HCC growth. 11,12 It has been described that D 9 -tetrahydrocannabinol (D 9 -THC), the main active constituent of marijuana, triggers human glioma cell death through stimulation of an ER stress pathway that activates autophagy and promotes apoptosis. 13,14 Autophagy is a cellular self-digestive process whereby bulk cytoplasmic components and intracellular organelles are sequestered into double-membrane vesicles named autophagosomes and delivered for degradation to the lysosomes.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

et al. 2011

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids -a novel family of potential anticancer agents -on the growth of HCC. We found that D 9 -tetrahydrocannabinol (D 9 -THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB 2 ) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB 2 receptor. We also found that D 9 -THC-and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase b was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that D 9 -THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC. Hepatocellular carcinoma (HCC) is one of the most common solid tumors and the third leading cause of cancer-related death worldwide. 1 Its prognosis remains reserved, with a 5-year survival rate of o5%. 2 It is the most common cause of death in patients with cirrhosis 3 and, according to the World Health Organization, the incidence of HCC is expected to increase until 2030. The overall survival of patients with HCC has not significantly improved in the past two decades. Current treatments are only applicable at early stages of tumor development and include tumor resection, liver transplantation, chemoembolization and sorafenib administration. 4 However, approximately half of the patients suffer tumor recurrence. The most important mechanism of liver cancer progression is cell proliferation. Although in recent years several clinical trials have tested the efficacy of agents that selectively target important signaling pathways involved in the control of this process, no relevant improvement in the prognostic/survival of patients with HCC has been achieved so far, 5 and, therefore, it is necessary to identify novel therapeutic strategies for the management of HCC.Cannabinoids are lipid mediators originally isolated from the hemp plant Cannabis sativa that produce their effects by activating primarily two G-protein-coupled receptors: cannabinoid receptor 1 (CB 1 ), which is highly abundant in the b...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

et al. 2011

View full text Add to dashboard Cite

show abstract

“…These mechanisms have been postulated in the pathogenesis of Alzheimer's disease and, therefore, cannabinoids may have beneficial effects in this disease [4,7,[13][14][15]. Additional mechanisms of action, including activation of peroxisome proliferator-activated receptors and modulation of mitochondrial activity and oxidative stress, could also contribute to cannabinoid-induced neuroprotection [19][20][21].…”

Section: Mj Casarejos Et Al / Pk −/− /Tau Vlw Mice and Phytocannabmentioning

confidence: 99%

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Casarejos

Perucho

Gómez

et al. 2013

JAD

108

View full text Add to dashboard Cite

Abstract. Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex ® , a mixture of 9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK −/− /Tau VLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex ® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex ® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK −/− /Tau VLW mice developed the neurological deficits, but those treated with Sativex ® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex ® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex ® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex ® reduced the deposition of both in the hippocampus and cerebral cortex of PK −/− /Tau VLW mice and increased autophagy. Sativex ® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK −/− /Tau VLW mice, a model of complex neurodegenerative disorders.

show abstract

“…AEA was found to induce apoptosis in Huh7 cells compared with vehicle. In HepG2 cells, AEA or the synthetic cannabinoid WIN induced hepatocyte apoptosis through the activation of proapoptotic signaling pathways (i.e., p38 MAPK and JNK) and inhibition of antiapoptotic signaling pathways (i.e., PKB/Akt), or via transcription factor PPARgamma (25,30). Furthermore, our data demonstrated that AEA upregulated Bak, which is a well-known cell death initiator in the apoptotic signaling cascade (31,32).…”

Section: Discussionmentioning

confidence: 59%

Anti-proliferative effects of anandamide in human hepatocellular carcinoma cells

Xie

Liu

et al. 2012

Oncology Letters

View full text Add to dashboard Cite

Abstract. In our previous study, we reported that the cannabinoid receptors CB1 and CB2 are overexpressed in human hepatocellular carcinoma (HCC) tissues. Recently, the antitumor potential of the endogenous cannabinoid anandamide (AEA) has also been addressed. The present study was conducted to investigate the anti-proliferative effects of AEA in HCC cells. The human HCC cell line Huh7 was used. Cell proliferation was measured by MTT assay and flow cytometry. Apoptotic analysis was investigated by TUNEL assay. Real-time PCR and western blot analysis were used to analyze the expression of relevant molecules. The results of this study demonstrated that AEA inhibited the proliferation of Huh7 cells, resulted in G1 cell cycle arrest and induced apoptosis. Furthermore, downregulation of CDK4 and upregulation of p21 and Bak by AEA were observed. This study defines the anti-proliferative effects of anandamide in HCC cells and suggests that AEA has therapeutic potential in the management of HCC patients.

show abstract

Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: Involvement of the transcription factor PPARγ

Cited by 62 publications

References 39 publications

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Anti-proliferative effects of anandamide in human hepatocellular carcinoma cells

Contact Info

Product

Resources

About