PI3K/ mTOR 抑制劑強化 cisplatin 及etoposide 抗腫瘤效果於人類小細胞肺癌之研究

Abstract

小細胞肺癌是所有種類的肺癌中最具侵略性的，約占所有肺癌的15至25百分比。儘管小細胞肺癌的病人在初次接受化學治療時相當有效，但幾乎難以避免的面臨短期內復發、短期轉移以及產生抗藥性等情況。因此目前極需新的治療策略：專一的標靶藥物輔助化學治療以達到更佳的治療效果。傳統上cisplatin及etoposide的合併治療是小細胞肺癌的第一線用藥，而NVP-BEZ235是一新型的標靶藥物，已經廣泛的試驗於多種癌症，目前於臨床試驗的第一、二階段。有鑑於此，本研究著重於測試PI3K/mTOR抑制劑： NVP-BEZ235是否能加強 cisplatin或etoposide 於小細胞肺癌的抗腫瘤效果以及其在訊息傳遞路徑上的表現。本研究結果證實在H146及H209的小細胞肺癌細胞株中，NVP-BEZ235分別合併cisplatin及etoposide皆表現明顯的抑制細胞增生效果以及誘發細胞凋亡。本研究進一步對訊息傳遞路徑進行分析，研究發現在PI3K/AKT/mTOR 訊息傳遞路徑中NVP-BEZ235 合併cisplatin或etoposide會影響AKT及 S6的磷酸化表現。除此之外，在H209細胞株中，絲胺酸473位置磷酸化的AKT在特定濃度的NVP-BEZ235下會大幅增加表現量。總結而言，本研究發現NVP-BEZ235和cisplatin或etoposide合併治療或許在小細胞肺癌治療上可作為一種新的標靶治療策略。

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer with poor prognosis, which accounts for 15-25% of all lung cancers. Despite initially sensitize to chemotherapy, relapse with metastasis in SCLC patients are almost inevitable within short duration and eventually develop drug resistance. Therefore, There is an urgent need for specific, targeted therapeutics in human small cell lung cancer. The purpose of our study is to investigate whether dual PI3K/mTOR inhibitor: NVP-BEZ235 potentiates cisplatin or etoposide anti-tumor effect and the interactions in signaling transduction in SCLC. Combination of cisplatin and etoposide has been used as SCLC first line treatment for about three decades, while NVP-BEZ235, now in phase I/II clinical trial, is a novel targeted agent and shows effect in various cancers. Our results demonstrate that the combination of NVP-BEZ235 and cisplatin/etoposide is effective in cytotoxicity and induce apoptosis in H146 and H209 cell lines. Furthermore, in the analysis of signaling pathways, combination of NVP-BEZ235 and cisplatin/etoposide influence the activation of AKT and S6 in PI3K/AKT/mTOR transduction cascade of SCLC. In addition, phosphorylated Ser473AKT increase in specific concentration of NVP-BEZ235 is observed in H209 cell line. In summary, our results suggest that NVP-BEZ235 may be a potential therapeutic targeted agent in cisplatin or etoposide mediated treatment in SCLC.