Kaewtunjai Navakoon, Wongpoomchai Rawiwan, Imsumran Arisa, Pompimon Wilart, Athipornchai Anan, Suksamrarn Apichart, Lee T Randall, Tuntiwechapikul Wirote
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Laboratory of Natural Products, Department of Chemistry, Faculty of Science and Center of Innovation in Chemistry, Lampang Rajabhat University, Lampang 52100, Thailand.
ACS Omega. 2018 Dec 27;3(12):18572-18581. doi: 10.1021/acsomega.8b02853. eCollection 2018 Dec 31.
Replicative senescence, which is caused by telomere shortening from the end replication problem, is considered one of the tumor-suppressor mechanisms in eukaryotes. However, most cancers escape this replicative senescence by reactivating telomerase, an enzyme that extends the 3'-ends of the telomeres. Previously, we reported the telomerase inhibitory effect of a crude extract (ZOE), which suppressed expression, leading to a reduction in hTERT protein and telomerase activity in A549 lung cancer cells. In the present study, we found that ZOE-induced telomere shortening and cellular senescence during the period of 60 days when these A549 cells were treated with subcytotoxic doses of ZOE. Using assay-guided fractionation and gas chromatography/mass spectrometry analysis, we found that the major compounds in the active subfractions were paradols and shogaols of various chain lengths. The results from studies of pure 6-paradol and 6-shogaol confirmed that these two compounds could suppress expression as well as telomerase activity in A549 cells. These results suggest that these paradols and shogaols are likely the active compounds in ZOE that suppress expression and telomerase activity in these cells. Furthermore, ZOE was found to be nontoxic and had an anticlastogenic effect against diethylnitrosamine-induced liver micronucleus formation in rats. These findings suggest that ginger extract can potentially be useful in dietary cancer prevention.
复制性衰老由端粒末端复制问题导致的端粒缩短引起，被认为是真核生物中的一种肿瘤抑制机制。然而，大多数癌症通过重新激活端粒酶来逃避这种复制性衰老，端粒酶是一种能延长端粒3'末端的酶。此前，我们报道了粗提物（ZOE）的端粒酶抑制作用，它抑制了相关表达，导致A549肺癌细胞中hTERT蛋白和端粒酶活性降低。在本研究中，我们发现当用亚细胞毒性剂量的ZOE处理这些A549细胞时，在60天内ZOE诱导了端粒缩短和细胞衰老。通过分析引导的分级分离和气相色谱/质谱分析，我们发现活性亚组分中的主要化合物是不同链长的姜辣素和姜烯酚。对纯6-姜辣素和6-姜烯酚的研究结果证实，这两种化合物可以抑制A549细胞中的相关表达以及端粒酶活性。这些结果表明，这些姜辣素和姜烯酚可能是ZOE中抑制这些细胞中相关表达和端粒酶活性的活性化合物。此外，发现ZOE无毒，并且对大鼠二乙基亚硝胺诱导的肝微核形成具有抗致突变作用。这些发现表明，生姜提取物在饮食性癌症预防中可能具有潜在用途。
