| 摘要: | 上皮性卵巢癌是婦科癌症當中最致命的一類。其預後不良的原因，部分是由於早期診斷不容易, 部分則是發生對於鉑類化學治療配方的抗藥性。到目前為止, 對於對鉑類化學治療配方有抗藥性的卵巢癌(鉑抗性卵巢癌), 尚無有效的治療, 因此, 新治療的研發一直都有所需求。細胞凋亡在癌症的控制方面扮演重要的角色, 然而針對細胞凋亡的卵巢癌治療尚無顯著進展。 JNK 和 PERK 是兩個和細胞受到壓力逼迫時相關的重要訊息傳遞途徑。為了探討 JNK 和 PERK 在鉑抗性卵巢癌被藥物引發細胞凋亡方面的角色, 我們使用nilotinib (AMN) 和evodiamine (EVO) 來進行研究。AMN 是第二代酪氨酸激酶抑制劑, 可抑制多種激酶並誘發細胞凋亡, EVO 則是從傳統中藥吳茱萸提煉出來, 曾被報導對於數種癌症細胞有誘發細胞凋亡的作用。我們發現 AMN 與 EVO 皆能誘發鉑抗性卵巢癌的細胞凋亡, 且對於非癌的細胞沒有太大的毒性。關於JNK, 我們發現其有雙重角色。 JNK 的活化, 並沒有加強 AMN 所誘發的細胞凋亡 (相反地, 有抗細胞凋亡的表現), 但是在EVO 所誘發的細胞凋亡上則有加強的作用。PERK 的活化, 則是加強誘導了EVO 所造成的鉑抗性卵巢癌細胞凋亡, 而在這過程當中, 我們也發現了PERK 和 JNK 有交互活化的現象。PERK 或可作為活化鉑抗性卵巢癌細胞凋亡途徑的一個標的。然而, JNK 則可能有雙面的作用而需審慎考量。此外, 含 EVO 之傳統中藥配方在鉑抗性卵巢癌之運用值得進一步探討。
Epithelial ovarian cancer is the most lethal gynecologic malignancy. One reason for its poor prognosis is the difficulty in early diagnosis, while the other reason is the development of resistance to platinum-based chemotherapy. For the time being, there is still no effective treatment for platinum-resistant epithelial ovarian cancer, and investigation for new treatment modality is always needed. Apoptosis plays an important role in cancer treatment, but there is no apoptosis-targeting treatment for ovarian cancer yet. To investigate the roles of two important stress-induced signaling pathway, JNK and PERK, in the drug-induced apoptosis of cisplatin-resistant epithelial ovarian cancer cells, nilotinib (AMN) and evodiamine (EVO) were used for our studies. AMN, a second-generation tyrosine kinase inhibitor, inhibits a broad spectrum of kinases and induces apoptosis. EVO, derived from the traditional herbal medicine Evodia rutaecarpa, has been reported to induce apoptosis in several types of cancer cells. We found that AMN and EVO were able to induce apoptosis and reduced the viability of cisplatin-resistant ovarian cancer cells, but not against non-cancerous cells. Regarding JNK, dual role was noted. JNK activation did not enhance AMN-induced apoptosis (and on the contrary, anti-apoptotic), while activation of JNK enhanced EVO-induced apoptosis. Activation of PERK enhanced the EVO-induced apoptosis of cisplatin-resistant ovarian cancer cells, and interaction between JNK and PERK was noted. We concluded that PERK could be considered for apoptosis-targeting treatment of cisplatin-resistant ovarian cancer, while JNK pathway could play dual roles and should be cautiously evaluated. In addition, EVO-containing traditional decoction for platinum-resistant ovarian cancer might warrant further investigation. |
