3′-羥基紫檀芪透過下調 JAK2/STAT3 訊號路徑抑制人類上皮性卵巢癌細胞之生長

Abstract

美國癌症協會American Cancer Society’s Center (ACS) 統計資料顯示，卵巢癌在美國女性癌症死亡中排名第五。在目前臨床治療上，化學療法是卵巢癌最常見的治療方法。有鑒於化療的缺點及其帶來的一些副作用，人們正在展望癌症化學治療的替代策略和全新分子機制。JAK2/STAT3 (The Janus kinase/signal transducer and activator of transcription) 訊號傳遞路徑是卵巢癌中的主要訊號通路之一，其與卵巢癌預後不良和腫瘤發展密切相關。紫檀芪（PSB）因其具有高生物利用度和抗腫瘤活性、低毒性而被廣泛研究，是一種有潛力的惡性腫瘤輔助治療劑。先前研究顯示，該化合物可有效抑制 STAT3 磷酸化，並且調控下游基因進一步誘發卵巢癌細胞週期停滯與細胞凋亡。3′-羥基紫檀芪（3′-HPSB）和2′-羥基紫檀芪（2′-HPSB）是紫檀芪的兩種羥基衍生物。然而，它們在卵巢癌中的抑制能力和潛在機制尚未闡明。因此，設計了兩種類型的人類卵巢癌細胞系模型和細胞株異種移植小鼠模型，藉以評估上述兩種化合物在細胞週期阻滯、凋亡及其可能分子機制方面對卵巢癌抗腫瘤作用進行探討。結果表明，在卵巢癌透明細胞型細胞株－TOV21G 中，3′-HPSB 可通過啟動 Caspase-3/Caspase-9 級聯反應和 PARP 誘導內源性凋亡，並通過下調 CDK1 和 Cyclin B1 的表現量導致 G2/M 期細胞週期停滯。此外，這種植物來源的化合物亦可通過下調JAK2/STAT3途徑的磷酸化來抑制STAT3核轉位。體內試驗研究表明，3′-HPSB 相比於PSB更能通過下調 JAK2/STAT3 訊號傳遞路徑並導致腫瘤細胞凋亡，從而降低 CDX 小鼠模型中的腫瘤生長且該化合物在小鼠臟器中未見無任何副作用。此外，在協同作用的測定上 3'-HPSB 可與第一線抗腫瘤藥物 Cisplatin 對透明細胞型卵巢癌進行有效性聯合治療的潛力。綜合以上所述紫檀芪與結構類似物中，3’-羥基紫檀芪相比於紫檀芪更可以作為一種有效治療透明細胞型卵巢癌潛在藥物。

According to statistical data of the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women, and at present, chemotherapy is the most common treatment for ovarian cancer. In light of the disadvantages of chemotherapy and several side effects that it may bring about, alternative strategies and brand new molecular mechanisms for cancer therapy are being looked forward. To be mentioned, JAK2/STAT3 pathway is one of the major signaling pathways in ovarian cancer which also be closely related to poor prognosis and tumor progression. Pterostilbene (PSB) is well-studied with its high bioavailability and strong antitumor activity, low toxicity, rendered as an attractive agent for adjuvant therapy in malignancies, which effectively suppressed phosphorylation of STAT3, as well as STAT3 downstream genes that regulate cell cycle and apoptosis in ovarian cancer. 3'-Hydroxypterostilbene (3′-HPSB) and 2'-Hydroxypterostilbene (2′-HPSB) are two of hydroxyl analogs of PSB. However, their inhibitory capability and underlying mechanism in ovarian carcinoma haven’t been clarified. Accordingly, a cell model with two types of human ovarian cancer cell lines and a cell line-derived xenograft mice model are designed to evaluate the anti-tumor effect of the above-mentioned compounds on ovarian cancer, in terms of cell cycle arrest, apoptosis, and its underlying possible molecular mechanisms. The results suggested that 3′-HPSB could lead to G2/M phase arrest by downregulating CDK1 and Cyclin B expressions. Besides, 3′-HPSB induced an intrinsic apoptosis pathway via activation of Caspase-3/Caspase-9 cascade and cleavege PARP and in clear cell ovarian carcinoma cell line－TOV21G. This compound could also inhibit the nuclear translocation of STAT3 via the reduction of phosphorylation of JAK2/STAT3 pathway. Moreover, the in vivo study showed that 3′-HPSB might have the potential to reduce tumor growth in CDX mice model by down-regulating JAK2/STAT3 pathway and leading tumor cell apoptosis without leading to adverse effect in organs. Overall, our result suggested that 3′-HPSB may be comparatively more effective than PSB in antitumor via inhibiting JAK2/STAT3 signal pathway. In addition, 3'- HPSB showed the potential to effectively synergize with the first-line anti-tumor drug Cisplatin in the treatment of clear cell ovarian cancer. Moreover, 3′-HPSB could be served as a novel anti-tumorigenesis agent on behalf of current therapy in clear cell ovarian carcinoma.