Cannabinoid combination targets NOTCH1-mutated T-cell acute lymphoblastic leukemia through the integrated stress response pathway

eLife, Journal Year: 2024, Volume and Issue: 12

Published: Sept. 11, 2024

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca 2+ . This is followed increased mRNA protein expression ATF4, CHOP, CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1 -mutated diseases cancers such as T-ALL.

Language: Английский

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Neuroprotective Effects of Cannabispirenone A against NMDA-Induced Excitotoxicity in Differentiated N2a Cells

Oxidative Medicine and Cellular Longevity, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 11

Published: May 31, 2024

The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 critical in preventing neurotoxicity caused by N-methyl-D-aspartate activation (NMDARs). activity of NMDARs places demands on endogenous to regulate their calcium currents. Endocannabinoids keep NMDAR within safe limits, protecting neural cells from excitotoxicity. Cannabinoids are remembered deliver this outcome repressing presynaptic glutamate discharge or obstructing postsynaptic NMDAR-managed flagging pathways. must exert a negative influence proportional strength signaling for such control be effective. goal paper draw attention towards neuroprotective mechanism constituents Cannabis sativa against NMDA-induced excitotoxic result. Phytochemical investigation cannabis flowers led isolation nine secondary metabolites. A spiro-compound, Cannabispirenone A, which treatment prior NMDA exposure significantly increases cell survival while decreasing ROS production, lipid peroxidation, intracellular calcium. Our findings showed that compound neuroprotection insult, has antioxidative properties, increased cannabinoid expression, may involved pathway neuroprotection.

Language: Английский

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Cannabinoid combination targets NOTCH1-mutated T-cell acute lymphoblastic leukemia through the integrated stress response pathway

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Dec. 14, 2023

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca2+. This is followed increased mRNA protein expression ATF4, CHOP, CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1-mutated diseases cancers such as T-ALL.

Language: Английский

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Cannabinoid Combination Targets NOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Published: March 4, 2024

In T-cell acute lymphoblastic leukemia (T-ALL) more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, Cannabidiol (CBD) and Cannabidivarin (CBDV); whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through Cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca 2+ . This is followed increased mRNA protein expression ATF4, CHOP CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight in-vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1 -mutated diseases cancers such as T-ALL.

Language: Английский

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Cannabinoid Combination TargetsNOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 21, 2023

Abstract In T-cell acute lymphoblastic leukemia (T-ALL) more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, Cannabidiol (CBD) and Cannabidivarin (CBDV); whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through Cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca 2+ . This is followed increased mRNA protein expression ATF4, CHOP CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight in-vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1 -mutated diseases cancers such as T-ALL.

Language: Английский

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Reviewer #1 (Public Review): Cannabinoid Combination Targets NOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Published: Dec. 14, 2023

In T-cell acute lymphoblastic leukemia (T-ALL) more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, Cannabidiol (CBD) and Cannabidivarin (CBDV); whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through Cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca2+. This is followed increased mRNA protein expression ATF4, CHOP CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight in-vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1-mutated diseases cancers such as T-ALL.

Language: Английский

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Cannabinoid Combination Targets NOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Published: Dec. 14, 2023

In T-cell acute lymphoblastic leukemia (T-ALL) more than 50% of cases display autoactivation Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar Cannabis that induces apoptosis by preventing maturation in cells. Here, we isolated three cannabinoids from this synergistically mimic the effects whole extract. Two were known, Cannabidiol (CBD) and Cannabidivarin (CBDV); whereas third cannabinoid, which termed 331-18A, was fully characterized study. demonstrated these act through Cannabinoid receptor type 2 TRPV1 activate integrated stress response pathway depleting intracellular Ca 2+ . This is followed increased mRNA protein expression ATF4, CHOP CHAC1, hindered inhibiting upstream initiation factor eIF2α. The abundance CHAC1 prevents maturation, thereby reducing levels active domain, consequently decreasing cell viability increasing apoptosis. Treatment with molecules resulted reduced tumor size weight in-vivo slowed progression mice models. Altogether, study elucidated mechanism action distinct modulating pathway, constitutes an important step establishment new therapy for treating NOTCH1 -mutated diseases cancers such as T-ALL.

Language: Английский

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