Antitumoral effects of cannabis in Notch1‐mutated T‐cell acute lymphoblastic leukemia

Abstract

R Antitumoral effects of cannabis in Notch1-mutated T-cell acute lymphoblastic leukemiaDear Editor,In T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic cancer with poor clinical outcomes, more than 50% of cases show NOTCH1-driven transformation [1]. The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages, ultimately causing the release of the active intracellular domain (NICD), which translocates to the nucleus where it promotes transcription of target genes involved in cell growth. The importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies. A new and promising emerging field in cancer treatment is medical cannabis. Accumulating evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models [2]. Cannabis, and its unique secondary metabolites, known as phytocannabinoids, directly affect the propagation of cancer cells by modulating key cellsignaling pathways [3]. We have previously demonstrated that different cannabis extracts, each containing a unique composition of metabolites, selectively impaired the survival of cancer cell lines depending on a match between the chemical composition of the extract and the characteristics of the specific cancer cell line [4]. In the present work, we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.We first performed a preliminary screening in which the viability of four distinct T-ALL cell lines was tested when

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

“…However, they were unable to identify the combinations of compounds that were responsible for this increased potency. In previous publications by our group, we showed that different CBD-rich Cannabis extracts, with equal amounts of CBD but varying concentrations of other minor compounds, lead to diverse anticonvulsant effects in a mouse model of epilepsy ( 29 ), and selective antitumoral effects in Notch1-mutated in T-ALL ( 32 ); suggesting the potential therapeutic effects of other compounds in the extracts in addition to CBD.…”

“…The CBD-rich extract was more potent than pure CBD or other high-CBD chemovars ( 32 ). This implied a specific combination of metabolites from the plant potentiate the full antitumor effect.…”

“…We have previously shown a specific CBD-rich Cannabis extract selectively induces apoptosis in T-ALL leukemia cell lines that harbor a NOTCH1 mutation. Treatment led to accumulation of the full-length immature form of Notch1 in the membrane, correspondingly with reduced NICD protein expression and transcription activity ( 32 ).…”

“…We further evaluated the anti-tumor properties of the three cannabinoids using several mouse models. The first model was a subcutaneous tumor model for which we have already demonstrated the effectivity of the whole extract ( 32 ). We engrafted subcutaneously Nonobese diabetic-severe combined immunodeficiency (NOD/Scid) mice with MOLT-4 cells, then treated with vehicle only or the combination of the cannabinoids from when tumors reached a volume of 100 mm 3 (day 7), on alternating days, for a duration of four weeks.…”

“…We have previously demonstrated that different Cannabis extracts with unique phytocannabinoid compositions impaired the survival and proliferation of specific cancer cell lines, suggesting that the effect of a particular Cannabis extract on a specific cancer cell line relies on its chemical composition ( 31 ). Following this framework, we successfully matched a specific CBD-rich Cannabis extract to T-ALL leukemia cells that harbor a NOTCH1 mutation ( 32 ). In the present study, we investigated which specific metabolites in the whole extract are responsible for T-ALL elimination, and elucidated the molecular mechanism by which they mediate their antitumor effects in this type of cancer.…”