Won Yen-Kim, Ong Choon-Nam, Shi Xianglin, Shen Han-Ming
Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Carcinogenesis. 2004 Aug;25(8):1449-58. doi: 10.1093/carcin/bgh151. Epub 2004 Mar 19.
Parthenolide (PN) is a major sesquiterpene lactone of feverfew (Tanacetum parthanium) with known anti-inflammatory activity. However, the anticancer effects of PN have not been well studied. In the present investigation, we examined the cancer chemopreventive property of PN using a combination of in vivo and in vitro approaches. We first tested the anticancer effect of PN in UVB-induced skin cancer model. Mice fed with PN (1 mg/day) showed a delayed onset of papilloma incidence, a significant reduction in papilloma multiplicity (papilloma/mouse) and sizes when compared with the UVB-only group. To our surprise, neither PN nor the known cyclooxygenase (COX)-2 inhibitor celecoxib inhibit UVB-induced COX-2 expression and epidermal prostaglandin E2 (PGE2) production. We next investigated the molecular mechanism(s) involved in its anticancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic concentrations of PN significantly inhibited UVB-induced activator protein-1 DNA binding and transcriptional activity. In addition, PN pre-treatment also inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More importantly, we found that impaired AP-1, JNK and p38 signaling led to the sensitization of JB6 cells to UVB-induced apoptosis. Data from our study for the first time confirm the anticancer property of PN in an animal model, and provide evidence that the inhibitory effects on AP-1 and mitogen-activated protein kinases serve as one of the underlying mechanisms for the cancer chemopreventive property of PN.
小白菊内酯（PN）是小白菊（Tanacetum parthanium）中的一种主要倍半萜内酯，具有已知的抗炎活性。然而，PN的抗癌作用尚未得到充分研究。在本研究中，我们结合体内和体外方法研究了PN的癌症化学预防特性。我们首先在紫外线B（UVB）诱导的皮肤癌模型中测试了PN的抗癌作用。与仅接受UVB照射的组相比，喂食PN（1毫克/天）的小鼠乳头状瘤发病率的起始延迟，乳头状瘤数量（每只小鼠的乳头状瘤数）和大小显著降低。令我们惊讶的是，PN和已知的环氧化酶（COX）-2抑制剂塞来昔布均未抑制UVB诱导的COX-2表达和表皮前列腺素E2（PGE2）的产生。接下来，我们使用培养的JB6小鼠表皮细胞研究了其抗癌作用所涉及的分子机制。非细胞毒性浓度的PN显著抑制UVB诱导的活化蛋白-1 DNA结合和转录活性。此外，PN预处理还抑制了c-Jun氨基末端激酶（JNK）和p38激酶的激活。更重要的是，我们发现AP-1、JNK和p38信号受损导致JB6细胞对UVB诱导的凋亡敏感。我们的研究数据首次证实了PN在动物模型中的抗癌特性，并提供证据表明对AP-1和丝裂原活化蛋白激酶的抑制作用是PN癌症化学预防特性的潜在机制之一。
