Cannabinoids and the Endocannabinoid System as Modulatory Targets in Neuroendocrine Neoplasms (NENs) – Possible Mechanisms and Antitumor Efficacy
2Department of Periodontics, Dental Medicine Faculty, Hadassah- Hebrew University Medical Organization
3Department of Cardiothoracic Surgery, Hadassah- Hebrew University Medical Organization
4Department of General Surgery, Mount Scopus, Hadassah- Hebrew University Medical Organization
5The Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, Hadassah- Hebrew University Medical Organization
Introduction:
Patients with unresectable NENs are offered a variety of non-curable therapeutic options, which eventually fail due to drug resistance (DR). Increasing evidence suggest an anticancer trait of cannabinoids, via cellular pathways including mTOR, known to be associated with DR development. Still, limited data exist on the anti-cancer effects of cannabinoids in NENs.
Aims:
To understand the possible anti-tumor role of the cannabinoids and the endocannabinoid system in NENs, and their ability to overcome resistance to everolimus (Eve).
Materials and Methods: The endocannabinoid receptors (ER) expression on NENs cell lines of lung (NCI-H727) and pancreatic (BON1) origin and on human samples was examined using FACS/immunofluorescence staining and RNA-Seq. Cells were treated with multiple cannabinoids extracts (CE). Viability and apoptosis were examined using WST-1 and Annexin/PI. ER blocking with specific antagonists examined CE-induced toxicity. The effect of Eve ± CE/ER-antagonists on cell viability was examined.
Results:
The ER CB1, but not CB2, is highly expressed in NEN cell lines and tumor samples. The expression of other ER (TRPV1, TRPV2, PPARα and PPARγ) is heterogeneous. 50 CE were initially tested, identifying 6 CE that significantly reduced cell viability by ~40% via CB1. Also, CB1 blocking vigorously decreased cells viability and increased apoptosis. Cells viability decreased by 15% with Eve alone; this effect was enhanced when CE and mainly CB1 antagonists were added (by 33% and 59%, respectively).
Conclusions:
Modulation of endocannabinoid system seems promising in NENs models, mostly via the ER CB1. Addition of CE/CB1 antagonist to Eve may have synergistic effects, with possible important therapeutic impact.
