Cafestol, one of the major components of coffee, is a coffee-specific diterpene form and an inhibitor of ERK2[1]. Cafestol has elevated blood lipids[2], anti-inflammatory[1], anti-angiogenic[3] and anti-diabetic[4] activities. In addition, Cafestol induces tumor cell apoptosis and autophagy, which can be used in the study of cancer[5].
In vitro, Cafestol (0–100μM; 1–24h) dose-dependently suppressed PGE₂ production and reduced COX-2 mRNA levels in LPS-stimulated RAW 264.7 cells, while concurrently inhibiting AP-1 activation and ERK2 activity after 1h treatment[1]. Cafestol (30μM, 24h) significantly potentiated ABT-737-induced apoptosis in Mcl-1-overexpressed human renal carcinoma Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells by downregulating Mcl-1 protein expression (via promoting protein degradation) and upregulating Bim expression, while showing no cytotoxicity in normal human skin fibroblasts[6].
In vivo, Cafestol (40–80mg/kg; i.g.; 20 days) markedly reduced tumor growth in a colon cancer xenograft mouse model[5]. Oral administration of Cafestol (5mg/kg/day for 14 days) in Wistar albino rats significantly protected against doxorubicin-induced cardiotoxicity by attenuating oxidative stress (downregulate MDA, upregulate GSH/SOD/CAT/Gpx-1), activating the Nrf2/HO-1/NQO-1 pathway (downregulate Keap1/NF-κB), suppressing inflammation (downregulate TNF-α/IL-1β), and inhibiting apoptosis (downregulate Bax/Casp3, downregulate TUNEL-positive cells), while improving cardiac biomarkers (CK-MB/LDH/ALP/ALT) and histopathology[7].
References:
[1] Shen, T., Lee, J., Lee, E., Kim, S. H., Kim, T. W., & Cho, J. Y. (2010). Cafestol, a coffee-specific diterpene, is a novel extracellular signal-regulated kinase inhibitor with AP-1-targeted inhibition of prostaglandin E2 production in lipopolysaccharide-activated macrophages. Biological & pharmaceutical bulletin, 33(1), 128–132.
[2] Urgert, R., Schulz, A. G., & Katan, M. B. (1995). Effects of cafestol and kahweol from coffee grounds on serum lipids and serum liver enzymes in humans. The American journal of clinical nutrition, 61(1), 149–154.
[3] Wang, S., Yoon, Y. C., Sung, M. J., Hur, H. J., & Park, J. H. (2012). Antiangiogenic properties of cafestol, a coffee diterpene, in human umbilical vein endothelial cells. Biochemical and biophysical research communications, 421(3), 567–571.
[4] Mellbye, F. B., Jeppesen, P. B., Shokouh, P., Laustsen, C., Hermansen, K., & Gregersen, S. (2017). Cafestol, a Bioactive Substance in Coffee, Has Antidiabetic Properties in KKAy Mice. Journal of natural products, 80(8), 2353–2359.
[5] Feng, Y., Yang, J., Wang, Y., Wang, X., Ma, Q., Li, Y., Zhang, X., Wang, S., Zhang, Q., Mi, F., Wang, Y., Zhong, D., & Yin, J. (2024). Cafestol inhibits colon cancer cell proliferation and tumor growth in xenograft mice by activating LKB1/AMPK/ULK1-dependent autophagy. The Journal of nutritional biochemistry, 129, 109623.
[6] Woo, S. M., Min, K. J., Seo, B. R., Nam, J. O., Choi, K. S., Yoo, Y. H., & Kwon, T. K. (2014). Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression. Cell death & disease, 5(11), e1514.
[7] Al-Kenany, S. A., & Al-Shawi, N. N. (2023). Protective effect of cafestol against doxorubicin-induced cardiotoxicity in rats by activating the Nrf2 pathway. Frontiers in pharmacology, 14, 1206782.
Cafestol是咖啡中主要活性成分之一，是一种咖啡特异性二萜类化合物，具有ERK2抑制活性[1]。Cafestol的药理作用包括升高血脂[2]、抗炎[1]、抗血管生成[3]及抗糖尿病[4]；此外，Cafestol可诱导肿瘤细胞凋亡与自噬，适用于癌症研究[5]。
体外实验中，Cafestol（0–100μM；1–24h）在脂多糖（LPS）刺激的RAW 264.7细胞中呈剂量依赖性抑制前列腺素E₂（PGE₂）生成并降低COX-2 mRNA水平，同时1小时处理即可抑制AP-1激活与ERK2活性[1]。30μM Cafestol处理24小时可通过下调Mcl-1蛋白（促进其降解）并上调Bim表达，显著增强ABT-737对Mcl-1过表达的人肾癌Caki细胞、胶质瘤U251MG细胞及乳腺癌MDA-MB231细胞的凋亡诱导作用，且对正常人皮肤成纤维细胞无毒性[6]。
体内实验中，Cafestol（40–80mg/kg；灌胃；20天）可显著抑制结肠癌异种移植小鼠模型的肿瘤生长[5]。Wistar大鼠连续14天口服Cafestol (5mg/kg/day)可通过减轻氧化应激（下调MDA，上调GSH/SOD/CAT/Gpx-1）、激活Nrf2/HO-1/NQO-1通路（下调Keap1/NF-κB）、抑制炎症（下调TNF-α/IL-1β）及凋亡（下调Bax/Casp3，下调TUNEL阳性细胞），同时改善心脏生物标志物（CK-MB/LDH/ALP/ALT）水平与组织病理损伤，显著缓解阿霉素诱导的心脏毒性[7]。