Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

Jia, Wentao; Hegde, Venkatesh L.; Singh, Narendra P.; Sisco, Daniel; Grant, Steven; Nagarkatti, Mitzi

doi:10.1158/1541-7786.mcr-05-0193

Cited by 78 publications

(66 citation statements)

References 65 publications

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“…Studies from our laboratory and others have established that THC and other cannabinoids can effectively suppress inflammatory response (Karsak et al, 2007;Michalski et al, 2007;Hegde et al, 2008;Jamontt et al, 2010). Moreover, we have also previously shown that THC can inhibit malignancies of the immune system (McKallip et al, 2002a;Lombard et al, 2005;Jia et al, 2006). Thus, cannabinoid receptors may be an excellent target candidate for use in graft-versus-leukemia treatment as well.…”

Section: Discussionmentioning

confidence: 76%

“…This is also the reason we have seen that agents such as THC that activate both CB1 and CB2 are more effective than CB1 or CB2 select agonists for causing immunosuppression. We have previously shown that activation of T cells with THC triggers molecular signaling involving down-regulation of Raf-1/mitogen-activated protein kinase/extracellular signalregulated kinase kinase/extracellular signal-regulated kinase/ribosomal kinase pathway, leading to translocation of Bad to mitochondria and this signaling can be inhibited by both CB1 or CB2 antagonists (Jia et al, 2006). Thus, we believe that the downstream signaling events after cannabinoid receptor activation are similar.…”

Section: Discussionmentioning

confidence: 82%

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Targeting Cannabinoid Receptors as a Novel Approach in the Treatment of Graft-versus-Host Disease: Evidence from an Experimental Murine Model

Pandey¹,

Hegde²,

Nagarkatti³

et al. 2011

J Pharmacol Exp Ther

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Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life-threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT often is accompanied by severe and lethal complications from graft-versus-host disease (GVHD), in which activated donor T cells recognize histocompatibility antigenic mismatches and cause significant toxicity in the recipient. In the current study, we tested the hypothesis that activation of cannabinoid receptors on donor-derived T cells may prevent GVHD. We tested the effect of ⌬ 9 -tetrahydrocannabinol (THC) in an acute model of GVHD that was induced by transferring parental C57BL/6 (B6) spleen cells into (C57BL/6 ϫ DBA/2) F 1 (BDF1) mice. Transfer of B6 cells into BDF1 mice produced severe acute GVHD in the recipient, characterized by lymphoid hyperplasia, weight loss, T helper l cytokine production and mortality. THC administration led to early recovery from body weight loss, reduced tissue injury in the liver and intestine, as well as complete survival. THC treatment reduced the expansion of donor-derived effector T cells and blocked the killing of host-derived immune cells while promoting Foxp3 ϩ regulatory T cells. Impaired hematopoiesis seen during GVHD was rescued by treatment with THC. The ability of THC to reduce the clinical GVHD was reversed, at least in part, by administration of cannabinoid receptor (CB) 1 and CB2 antagonists, thereby demonstrating that THC-mediated amelioration of GVHD was cannabinoid receptor-dependent. Our results demonstrate for the first time that targeting cannabinoid receptors may constitute a novel treatment modality against acute GVHD.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 82%

Targeting Cannabinoid Receptors as a Novel Approach in the Treatment of Graft-versus-Host Disease: Evidence from an Experimental Murine Model

Pandey¹,

Hegde²,

Nagarkatti³

et al. 2011

J Pharmacol Exp Ther

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“…Although anticancer studies involving CANNs have rightly concentrated on cancers of the brain (21), a number have focused on their efficacy in leukaemias (13,22,23). Earlier investigations studied the action of THC alone in leukaemia, but limitations to the dosages that could be used in patients due to the psychoactivity associated with its use, made THC unattractive.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration

Scott

Dalgleish

Liu

2017

International Journal of Oncology

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Abstract. Phytocannabinoids possess anticancer activity when used alone, and a number have also been shown to combine favourably with each other in vitro in leukaemia cells to generate improved activity. We have investigated the effect of pairing cannabinoids and assessed their anticancer activity in cell line models. Those most effective were then used with the common anti-leukaemia drugs cytarabine and vincristine, and the effects of this combination therapy on cell death studied in vitro. Results show a number of cannabinoids could be paired together to generate an effect superior to that achieved if the components were used individually. For example, in HL60 cells, the IC 50 values at 48 h for cannabidiol (CBD) and tetrahydrocannabinol (THC) when used alone were 8 and 13 µM, respectively; however, if used together, it was 4 µM. Median-effect analysis confirmed the benefit of using cannabinoids in pairs, with calculated combination indices being <1 in a number of cases. The most efficacious cannabinoid-pairs subsequently synergised further when combined with the chemotherapy agents, and were also able to sensitise leukaemia cells to their cytotoxic effects. The sequence of administration of these drugs was important though; using cannabinoids after chemotherapy resulted in greater induction of apoptosis, whilst this was the opposite when the schedule of administration was reversed. Our results suggest that when certain cannabinoids are paired together, the resulting product can be combined synergistically with common anti-leukaemia drugs allowing the dose of the cytotoxic agents to be dramatically reduced yet still remain efficacious. Nevertheless, the sequence of drug administration is crucial to the success of these triple combinations and should be considered when planning such treatments.

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“…259 THC-induced apoptosis in Jurkat leukemia T cells was found to be regulated by translocation of Bad to mitochondria. 260 Exposure of leukemia cells to CBD led to CB2-mediated reduction in cell viability and induction in apoptosis (although CBD is considered not to bind to either CB1 or CB2 receptors). It is noteworthy that CBD exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22(phox).…”

Section: Cancermentioning

confidence: 99%

Cannabinoids in Health and Disease

2016

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annabis sativa L. preparations, such as marijuana, hashish, and dagga, have been used in medicine for millenia.1 Investigations into the chemistry of Cannabis began in the mid-19th century, following a major trend in chemical research at the time, which centered on the quest for active natural products. Numerous alkaloids were isolated in pure form from various plants, and many of them were fully or partially characterized. Morphine, cocaine, strychnine, and many others were purified and used in medicine. However, most of the terpenoids-a major class of secondary plant metabolites, to which the plant cannabinoids also belong-were not isolated until the end of the century or even much later, and in many cases their purity was doubtful. 413C l i n i c a l r e s e a r c h

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Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

Cited by 78 publications

References 65 publications

Targeting Cannabinoid Receptors as a Novel Approach in the Treatment of Graft-versus-Host Disease: Evidence from an Experimental Murine Model

Targeting Cannabinoid Receptors as a Novel Approach in the Treatment of Graft-versus-Host Disease: Evidence from an Experimental Murine Model

Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration

Cannabinoids in Health and Disease

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