PO.CH01.05 · 化学
咖啡二萜类化合物咖啡醇乙酸酯和咖啡豆醇对紫杉烷耐药性及神经内分泌性前列腺癌细胞的抗肿瘤作用
Antitumor effects of coffee diterpenes, kahweol acetate and cafestol, on taxane-resistant and neuroendocrine prostate cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：流行病学研究报道，较高的咖啡消费量与前列腺癌风险降低相关。咖啡醇乙酸酯（kahweol acetate）和咖啡豆醇（cafestol）是未过滤咖啡中的主要二萜类化合物，已在前列腺癌细胞中显示出抗肿瘤活性。然而，它们对治疗耐药亚型的作用尚不明确，包括紫杉烷耐药的去势抵抗性前列腺癌（CRPC）和神经内分泌性前列腺癌（NEPC）。针对这些侵袭性变异型的治疗选择仍极为有限，凸显出对新型药物的需求。我们旨在研究咖啡醇乙酸酯和咖啡豆醇在这些难治性前列腺癌模型中的抗肿瘤潜力及其内在机制。
方法：我们使用了多西他赛耐药（DU145-TxR、PC-3-TxR）和卡巴他赛耐药（DU145-TxR/CxR、PC-3-TxR/CxR）前列腺癌细胞系，它们分别由相应的亲本DU145和PC-3细胞建立。此外，还纳入了神经内分泌性前列腺癌细胞系NCI-H660。细胞以咖啡醇乙酸酯和/或咖啡豆醇（10-100 μM）处理。评估了细胞增殖和迁移。采用联合指数-等效线图法分析协同作用。通过流式细胞术评估凋亡诱导和细胞周期分布。通过蛋白质免疫印迹检测凋亡相关蛋白（cleaved-caspase-3、cleaved-PARP、Bcl-2、Bcl-xL）和EMT相关蛋白（Snail、Slug）的表达。
结果：咖啡醇乙酸酯和咖啡豆醇均以剂量依赖方式显著抑制所有耐药和NEPC细胞系的增殖和迁移。联合处理（各30 μM）产生协同抑制作用。流式细胞术显示sub-G1群体增加，G2期减少，提示凋亡诱导。蛋白质免疫印迹显示cleaved-caspase-3和cleaved-PARP表达增加，同时抗凋亡的Bcl-2和Bcl-xL水平下降。EMT标志物Snail和Slug亦下调，表明迁移潜能受到抑制。
结论：咖啡醇乙酸酯和咖啡豆醇通过协同诱导凋亡和抑制EMT，在紫杉烷耐药性及神经内分泌性前列腺癌细胞中发挥强效抗肿瘤作用。鉴于它们在临床可达到的浓度下即具疗效，这些咖啡来源的二萜类化合物代表着治疗耐药性前列腺癌新型治疗方法的有前景的候选药物。
查看英文原文 English abstract
Background: Epidemiological studies have reported that higher coffee consumption is associated with a reduced risk of prostate cancer. Kahweol acetate and cafestol, major diterpenes found in unfiltered coffee, have shown antitumor activity in prostate cancer cells. However, their effects on treatment-resistant subtypes, including taxane-resistant castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remain unclear. Therapeutic options for these aggressive variants remain extremely limited, highlighting the need for novel agents. We aimed to investigate the antitumor potential and underlying mechanisms of kahweol acetate and cafestol in these refractory prostate cancer models.
Methods: We used docetaxel-resistant (DU145-TxR, PC-3-TxR) and cabazitaxel-resistant (DU145-TxR/CxR, PC-3-TxR/CxR) prostate cancer cell lines, which were established from their respective parental DU145 and PC-3 cells. In addition, the neuroendocrine prostate cancer cell line NCI-H660 was included. Cells were treated with kahweol acetate and/or cafestol (10-100 μM). Cell proliferation and migration were evaluated. Synergistic effects were analyzed using the combination index-isobologram method. Apoptosis induction and cell cycle distribution were evaluated by flow cytometry. Expression of apoptosis-related (cleaved-caspase-3, cleaved-PARP, Bcl-2, Bcl-xL) and EMT-related (Snail, Slug) proteins was examined by western blotting.
Results: Both kahweol acetate and cafestol significantly inhibited proliferation and migration in all resistant and NEPC cell lines in a dose-dependent manner. Combined treatment (30 μM each) produced synergistic inhibition. Flow cytometry demonstrated an increased sub-G1 population and a reduced G2 phase, suggesting apoptosis induction. Western blotting revealed increased cleaved-caspase-3 and cleaved-PARP expression, along with decreased anti-apoptotic Bcl-2 and Bcl-xL levels. EMT markers Snail and Slug were also downregulated, indicating suppression of migratory potential.
Conclusions: Kahweol acetate and cafestol exert strong antitumor effects in taxane-resistant and neuroendocrine prostate cancer cells through synergistic induction of apoptosis and inhibition of EMT. Given their efficacy at clinically achievable concentrations, these coffee-derived diterpenes represent promising candidates for novel therapeutic approaches in treatment-resistant prostate cancer.
利益披露 Disclosure
T. Hori, None..
H. Iwamoto, None..
T. Kamjima, None..
H. Kano, None..
M. Tomoyuki, None..
R. Naito, None..
H. Yaegashi, None..
K. Shigehara, None..
T. Nohara, None..
K. Izumi, None..
A. Mizokami, None.