Cannabinoids and Gliomas

Velasco, Guillermo; Carracedo, Arkaitz; Blázquez, Cristina; Lorente, Mar; Aguado, Tania; Haro, Amador; Sánchez, Cristina; Galve‐Roperh, Ismael; Guzmán, Manuel

doi:10.1007/s12035-007-0002-5

Cited by 79 publications

(62 citation statements)

References 64 publications

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“…Recently, numerous studies have evidenced the role of cannabinoids as potential anti-tumoral drugs owing to their ability to reduce tumor in different animal models, including glioma, 6 breast cancer 7,8 and prostate cancer. 9,10 Recent research has also reported that the synthetic cannabinoid WIN-55 212-2 inhibits HCC growth.…”

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confidence: 99%

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

et al. 2011

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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...

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

et al. 2011

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“…THC but not CBD has been shown to engage cannabinoid receptors to promote tumor cell death (16,23,34). Thus, THC triggers the accumulation of de novo-synthesized ceramide, which leads in turn to stimulation of autophagy and apoptosis (15).…”

Section: Combined Treatment With Thc and Cbd Greatly Enhances Glioma mentioning

confidence: 99%

“…Among these therapeutic applications, cannabinoids are being investigated as antitumoral agents (11,12). Thus, cannabinoid administration curbs the growth of several types of tumor xenografts in rats and mice (11,12) including gliomas (13)(14)(15)(16). On the basis of this preclinical evidence, a pilot clinical trial has been recently conducted to investigate the antitumoral action of THC on recurrent gliomas (17).…”

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A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

Torres

Lorente²,

Rodríguez-Fornés³

et al. 2011

Molecular Cancer Therapeutics

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Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. D 9 -Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ þ THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM. Mol Cancer Ther; 10(1); 90-103. Ó2011 AACR.

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“…The fact that lipoprotein-derived endocannabinoids help to repress such an important tumor-promoting pathway suggests new possibilities to explain the link between disturbed lipoprotein metabolism and cancer risk [32]. In fact, cannabinoids block the growth of many tumors known to depend on Hh signaling [33,34,35,36,37,38,39,40].…”

Section: Spectrometry (Ms/ms) and Thin Layer Chromatography (Tlc) Msmentioning

confidence: 99%