Division of Physiology, Department of Nutrition, Graduate School of Humanity and Life Science, Tokyo-Kasei University, 1-18-1 Kaga, Itabashi-ku, Tokyo, 1738602, Japan; Megumi Home Clinic, 2-4-3 Hashido, Seya-ku, Yokohama-city, Kanagawa, 2460037, Japan.
Medical Health Evaluation and Promotion Center, Fujisawa-Junten Clinic, 1-17-11 Kugenumatachibana, Fujisawa-city, Kanagawa, 2510024, Japan.
Clin Nutr ESPEN. 2023 Jun;55:20-29. doi: 10.1016/j.clnesp.2023.02.020. Epub 2023 Mar 2.
BACKGROUND & AIMS: Endocannabinoids (eCBs) are involved in various physiological functions such as appetite, metabolism, and inflammation. Although deterioration of these functions is often observed in patients with refractory cancer cachexia (RCC), the relationship between circulating eCBs and cancer cachexia remains unknown. This study aimed to evaluate the relationship between circulating levels of eCBs and clinical findings in patients with RCC.
Circulating N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) levels were measured in 39 patients with RCC (36% females, median age and IQR: 79 and 69-85), and 18 age- and sex-matched controls who received medical therapy for non-communicable diseases, using liquid chromatography with tandem mass spectrometry. In the RCC group, relationships between eCB levels and clinical findings-such as anorexia, awareness of pain, performance status, and survival period-were also examined. As anti-inflammatory drugs can influence the action and metabolism of eCBs, the following two analyses were conducted. In analysis 1, all participants were included, and in analysis 2, participants receiving any anti-inflammatory drugs were excluded.
Serum AEA and 2-AG levels were more than twice as high in the RCC group than in those in the control group in both analyses. In analysis 1, only 8% of patients reported normal appetite assessed using the numerical rating scale (NRS), and serum AEA levels were negatively correlated with the NRS scores (R = -0.498, p = 0.001). Serum 2-AG levels were positively correlated with serum triglyceride levels (R = 0.419, p = 0.008). Both AEA and 2-AG levels were positively correlated with serum C-reactive protein (CRP) levels (AEA: R = 0.516, p < 0.001; 2-AG: R = 0.483, p = 0.002). Multiple linear regression analysis in the form of a stepwise procedure was performed; NRS scores and CRP levels showed a significant association with AEA levels (NRS: p = 0.001; CRP: p < 0.001), with an adjusted R value of 0.426. Similarly, triglyceride and CRP levels showed a significant association with the log of 2-AG levels (triglycerides: p < 0.001; CRP: p < 0.001), with an adjusted R value of 0.442. In analysis 2, serum AEA levels were negatively correlated with the NRS scores (R = -0.757, p < 0.001), whereas serum triglyceride levels were positively correlated with 2-AG levels (R = 0.623, p = 0.010).
Circulating eCB levels were significantly higher in patients with RCC than those in controls. In patients with RCC, circulating AEA may play a role in anorexia, whereas 2-AG may play a role in serum triglyceride levels.
内源性大麻素（eCBs）参与了多种生理功能，如食欲、代谢和炎症。尽管这些功能在难治性癌症恶病质（RCC）患者中经常恶化，但循环 eCBs 与癌症恶病质之间的关系仍不清楚。本研究旨在评估 RCC 患者循环 eCB 水平与临床发现之间的关系。
使用液质联用技术测量了 39 名 RCC 患者（女性占 36%，中位年龄和 IQR：79 和 69-85）和 18 名年龄和性别匹配的接受非传染性疾病药物治疗的对照组的循环 N-花生四烯酸乙醇胺（anandamide，AEA）和 2-花生四烯酸甘油（2-AG）水平。在 RCC 组中，还检查了 eCB 水平与临床发现之间的关系，如厌食、疼痛感知、表现状态和生存时间。由于抗炎药物可能会影响 eCB 的作用和代谢，因此进行了以下两项分析。在分析 1 中，包括了所有参与者，在分析 2 中，排除了使用任何抗炎药物的参与者。
在这两项分析中，RCC 组患者的血清 AEA 和 2-AG 水平均高于对照组两倍以上。在分析 1 中，只有 8%的患者使用数字评分量表（NRS）报告正常食欲，血清 AEA 水平与 NRS 评分呈负相关（R=-0.498，p=0.001）。血清 2-AG 水平与血清甘油三酯水平呈正相关（R=0.419，p=0.008）。AEA 和 2-AG 水平均与血清 C 反应蛋白（CRP）水平呈正相关（AEA：R=0.516，p<0.001；2-AG：R=0.483，p=0.002）。采用逐步程序的多元线性回归分析；NRS 评分和 CRP 水平与 AEA 水平呈显著相关性（NRS：p=0.001；CRP：p<0.001），调整后的 R 值为 0.426。同样，甘油三酯和 CRP 水平与 2-AG 水平的对数呈显著相关性（甘油三酯：p<0.001；CRP：p<0.001），调整后的 R 值为 0.442。在分析 2 中，血清 AEA 水平与 NRS 评分呈负相关（R=-0.757，p<0.001），而血清甘油三酯水平与 2-AG 水平呈正相关（R=0.623，p=0.010）。
RCC 患者的循环 eCB 水平明显高于对照组。在 RCC 患者中，循环 AEA 可能在厌食中起作用，而 2-AG 可能在血清甘油三酯水平中起作用。
