Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation

Galve‐Roperh, Ismael; Sánchez, Cristina; Cortés, Maria L.; Izquierdo, Marta López; Guzmán, Manuel

doi:10.1038/73171

Cited by 631 publications

(613 citation statements)

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“…47,48 However, recent studies have shown that ERK activation may also result in cell cycle arrest, emphasizing that the responses may differ depending on the cell type and nature of the extracellular signal and its duration. [49][50][51][52] In addition, the timing and actual amounts of ZBP-89 protein generated might modulate which downstream kinase is activated. Similar to our findings with ZBP-89, overexpression of BRCA1 in MCF-7 breast cancer cells also activates both JNK (proapoptotic) and ERK (antiapoptotic) pathways, and MEK1/2 inhibition enhances BRCA1-induced apoptosis.…”

Section: Ibmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

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Section: Ibmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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“…We have previously shown that cannabinoids inhibit the growth (Galve-Roperh et al, 2000;Sánchez et al, 2001) and angiogenesis (Blázquez et al, 2003(Blázquez et al, , 2004 of gliomas in animal models. Remarkably, this antiproliferative effect seems to be selective for brain-tumour cells as the survival of normal brain cells (astrocytes (Gómez del Pulgar et al, 2002), oligodendrocytes (Molina-Holgado et al, 2002) and neurons ) is unaffected or even favoured by cannabinoid challenge.…”

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confidence: 96%

A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

et al. 2006

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D 9 -Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15 -33). D 9 -Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumourcell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

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“…Central type I CB, cloned in 1990 [26], is predominantly expressed in the brain [27], while peripheral type II CB, cloned in 1993 [28], is mainly expressed in cells of immune origin [29]. In recent years, cannabinoids, the active components of Cannabis sativa Linnaeus (Marijuana), and their derivatives have received renewed attention due to their diverse pharmacologic activities, such as cell growth inhibition, antiinflammatory effects, and tumor regression [30][31][32][33][34]. However, the molecular mechanisms by which these compounds exert their pharmacologic effects remain to be established.…”

Section: Discussionmentioning

confidence: 99%