Terpinen-4-ol：一种用于人类胃肠道肿瘤的新颖有前途的治疗剂。,PLOS ONE

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Terpinen-4-ol：一种用于人类胃肠道肿瘤的新颖有前途的治疗剂。
PLOS ONE ( IF 2.9 ) Pub Date : 2016-06-09 , DOI: 10.1371/journal.pone.0156540
Shiran Shapira ₁ , Shlomo Pleban ₂ , Diana Kazanov ₁ , Peter Tirosh ₂ , Nadir Arber ₁

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背景技术天然存在的单萜萜品醇-4-醇是茶树油的主要生物活性成分，并已被证明具有许多生物活性。目的研究单独或与化学治疗和生物制剂联合使用时，萜品四醇的抗肿瘤作用及其在前列腺和胃肠道恶性肿瘤中的作用机理。方法将Terpinen-4-ol单独或与标准化疗（奥沙利铂，氟尿嘧啶，吉西他滨，特罗凯）和生物制剂（西妥昔单抗）联合给药。它还与人源化抗CD24 mAb结合（由我们开发）。治疗结直肠，胰腺，胃，前列腺癌细胞后，通过光学显微镜定性测定杀伤作用，并使用MTT和FACS分析定量测定杀伤作用。在异种移植模型中评估了Terpinen-4-ol对肿瘤发展的影响。结果Terpinen-4-ol以剂量依赖方式（10-90％，0.005-0.1％）诱导显着抑制结直肠癌，胰腺癌，前列腺癌和胃癌细胞的生长。Terpinen-4-ol和各种抗癌药（0.2μM的奥沙利铂和0.5μM的氟尿嘧啶）显示出对癌细胞增殖的协同抑制作用（分别为83％和91％）。在抗EGFR治疗耐药的KRAS突变大肠癌细胞中，将萜品四醇与西妥昔单抗（1μM）结合使用可产生令人印象深刻的80-90％的生长抑制效果。萜品醇4-ol的亚毒性浓度可增强抗CD24 mAb（150μg/ ml）诱导的生长抑制（90％）。萜品醇4-ol后肿瘤体积显着减少（0。与对照组相比，仅2％）的治疗和西妥昔单抗（10mg / kg）的治疗（分别为40％和63％）。结论Terpinen-4-ol可显着增强几种化学治疗剂和生物制剂的作用。其活性的可能分子机制包括诱导细胞死亡，从而使该化合物单独成为潜在的抗癌药物，并与多种恶性肿瘤联合治疗。Terpinen-4-ol可恢复具有KRAS突变的癌症中西妥昔单抗的活性。其活性的可能分子机制包括诱导细胞死亡，从而使该化合物单独成为潜在的抗癌药物，并与多种恶性肿瘤联合治疗。Terpinen-4-ol可恢复具有KRAS突变的癌症中西妥昔单抗的活性。其活性的可能分子机制包括诱导细胞死亡，从而使该化合物单独成为潜在的抗癌药物，并与多种恶性肿瘤联合治疗。Terpinen-4-ol可恢复具有KRAS突变的癌症中西妥昔单抗的活性。

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Terpinen-4-ol: A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers.

BACKGROUND Terpinen-4-ol, a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities. AIM To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies, alone and in combination with chemotherapeutic and biological agents. METHODS Terpinen-4-ol was administrated alone or combined with standard chemotherapy (Oxaliplatin, Fluorouracil, Gemcitabine, Tarceva) and biological agent (Cetuximab). It was also combined with humanized anti-CD24 mAbs (was developed by us). Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis, following treatment of colorectal, pancreatic, gastric and prostate cancer cells. Terpinen-4-ol effect on tumor development was evaluated in xenograft model. RESULTS Terpinen-4-ol induces a significant growth inhibition of colorectal, pancreatic, prostate and gastric cancer cells in a dose-dependent manner (10-90% in 0.005-0.1%). Terpinen-4-ol and various anti-cancer agents (0.2μM oxaliplatin and 0.5μM fluorouracil) demonstrated a synergistic inhibitory effect (83% and 91%, respectively) on cancer cell proliferation. In KRAS mutated colorectal cancer cells, which are resistant to anti-EGFR therapy, combining of terpinen-4-ol with cetuximab (1 μM) resulted in impressive efficacy of 80-90% growth inhibition. Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb (150μg/ml)-induced growth inhibition (90%). Considerable reduction in tumor volume was seen following terpinen-4-ol (0.2%) treatment alone and with cetuximab (10mg/kg) (40% and 63%, respectively) as compare to the control group. CONCLUSION Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. The possible molecular mechanism for its activity involves induction of cell-death rendering this compound as a potential anti-cancer drug alone and in combination in the treatment of numerous malignancies. Terpinen-4-ol restores the activity of cetuximab in cancers with mutated KRAS.

更新日期：2019-11-01

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