神经内分泌肿瘤、嗜铬细胞瘤/副神经节瘤原代培养中，大麻二酚的拮抗作用。

Opposing Effects of Cannabidiol in Patient-derived Neuroendocrine Tumor, Pheochromocytoma/Paraganglioma Primary Cultures.

机构信息

Department of Internal Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany.

Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, CH-8091 Zurich, Switzerland.

出版信息

J Clin Endocrinol Metab. 2024 Oct 15;109(11):2892-2904. doi: 10.1210/clinem/dgae241.

DOI:10.1210/clinem/dgae241

PMID:38605427

Abstract

CONTEXT

Treatment options for advanced neuroendocrine tumors (NETs), pheochromocytomas and paragangliomas (PPGLs) are still limited. In recent years, antitumor effects of cannabinoids have been reported; however, there are only very limited data available in NETs or PPGLs.

OBJECTIVE

Investigation of the effects of cannabidiol (CBD) on patient-derived human NET/PPGL primary cultures and on NET/PPGL cell lines.

METHODS

We established primary cultures derived from 46 different patients with PPGLs (n = 35) or NETs (n = 11) who underwent tumor resection at 2 centers. Treatment of patient primary cultures with clinically relevant doses (5 µM) and slightly higher doses (10 µM) of CBD was performed.

RESULTS

We found opposing effects of 5 µM CBD: significant antitumor effects in 5/35 (14%) and significant tumor-promoting effects in 6/35 (17%) of PPGL primary cultures. In terms of antitumor effects, cluster 2-related PPGLs showed significantly stronger responsivity to CBD compared to cluster 1-related PPGLs (P = .042). Of the cluster 2-related tumors, NF1 PPGLs showed the strongest responsivity (4/5 PPGL primary cultures with a significant decrease in cell viability were NF1-mutated). We also found opposing effects of 10 µM CBD in PPGLs and NETs: significant antitumor effects in 9/33 of PPGL (27%) and 3/11 of NET (27%) primary cultures and significant tumor-promoting effects in 6/33 of PPGL (18%) and 2/11 of NET (18%) primary cultures.

CONCLUSION

We suggest a potential novel treatment option for some NETs/PPGLs but also provide evidence for caution when applying cannabinoids as supportive therapy for pain or appetite management to cancer patients and possibly as health supplements.

摘要

背景

晚期神经内分泌肿瘤（NETs）、嗜铬细胞瘤和副神经节瘤（PPGLs）的治疗选择仍然有限。近年来，已有报道称大麻素具有抗肿瘤作用；然而，NETs 或 PPGLs 中仅有非常有限的数据可用。

目的

研究大麻二酚（CBD）对患者来源的人 NET/PPGL 原代培养物和 NET/PPGL 细胞系的影响。

方法

我们在 2 个中心建立了来自 46 名接受肿瘤切除术的 PPGL（n = 35）或 NET（n = 11）患者的原代培养物。用临床相关剂量（5 μM）和略高剂量（10 μM）的 CBD 处理患者原代培养物。

结果

我们发现 5 μM CBD 具有相反的作用：在 35 个 PPGL 原代培养物中的 5/35（14%）中具有显著的抗肿瘤作用，在 35 个中的 6/35（17%）中具有显著的促肿瘤作用。在抗肿瘤作用方面，与 cluster 1 相关的 PPGLs 相比，cluster 2 相关的 PPGLs 对 CBD 的反应性明显更强（P =.042）。在 cluster 2 相关的肿瘤中，NF1 PPGLs 表现出最强的反应性（5 个 PPGL 原代培养物中有 4 个细胞活力明显下降，为 NF1 突变）。我们还发现 10 μM CBD 在 PPGLs 和 NETs 中具有相反的作用：在 33 个 PPGL 原代培养物中的 9/33（27%）和 11 个 NET 原代培养物中的 3/11（27%）中具有显著的抗肿瘤作用，在 33 个 PPGL 原代培养物中的 6/33（18%）和 11 个 NET 原代培养物中的 2/11（18%）中具有显著的促肿瘤作用。