MAPK激酶抑制劑加強 etoposide及 ABT-737在小細胞肺癌的細胞毒殺效果之研究

Abstract

小細胞肺癌(SCLC)具有不同於非小細胞肺癌(NSCLC)的侵略性特質，在世界所有診斷的肺癌中佔有約13%的比率。化學療法合併放射線治療是現在治療小細胞肺癌的最常使用的方式。雖然初始的治療反應很好，但是由於復發及抗藥性的發生率很高，造成小細胞肺癌患者極低的存活率。在過去幾十年來，小細胞肺癌的存活率只有輕微的改善，因此投入結合標靶藥物與有效的治療藥物的研究日益漸增，希望藉由與具有較低毒性的標靶藥物結合，提升治療藥物的治療效果、並且預防抗藥性的產生來改善小細胞肺癌的存活率。在本篇的研究當中，我們透過結合MEK 抑制劑 CI-1040抑制在調節細胞生理功能具有重要地位，且同時與小細胞肺癌癌化過程相關的mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) 訊息傳遞路徑，作為治療小細胞肺癌新穎的治療策略。鑒於CI-1040具有抑制小細胞肺癌細胞生長之活性，我們利用CI-1040與eoposide和ABT-737兩種藥物結合，以實驗MAPK/ERK 訊息傳遞路徑是否與小細胞癌症細胞對於此兩種藥物的反應有所關連進而影響藥物效果。Etoposide 是一種經常被使用的化療藥物；而ABT-737是一種Bcl-2的抑制劑，具有引起細胞凋亡的能力，此兩種藥物皆具有對於小細胞肺癌的毒殺效果。此篇研究的結果指出CI-1040可以透過干涉細胞週期的進行以及促進細胞凋亡的方式去加強此兩者藥物對於小細胞肺癌細胞生長的抑制效果。此外，藥物對於PI3K/AKT 訊息傳遞路徑具有交互影響也是牽涉於其中的機制。因此，MAPK/ERK訊息傳遞路徑的抑制可以作為一種加強小細胞肺癌的治療藥物的方式。

Small cell lung cancer (SCLC), exhibiting aggressive characteristics which differ from its counterpart non-small cell lung cancer (NSCLC), accounts for 13% of all lung cancer type worldwide. Chemotherapy coupling with radiotherapy remain the general management applied for SCLC treatment. Despite of good initial response, frequent relapse and resistance occurrence resulting in poor survival rate. With modest but no significant advance on survival for the past decades, growing attention have been paid on combining targeted therapy with effective therapeutic agents aiming for reinforcing drug response and overcoming resistance with lower toxic target drugs. In this study, we target inhibition of mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathway with MEK inhibitor CI-1040 as a novel strategy for SCLC treatment. MAPK/ERK pathway not only plays an important role regulating multiple cellular processes which may determine sensitivities toward therapeutic drugs but also involves in pathogenesis of SCLC. With CI-1040 employment inhibiting cell proliferation in SCLC, experiment of combo treatment with etoposide and ABT-737 are carried out to investigate whether MAPK/ERK pathway takes part in cellular response. Etoposide, a wildly applied chemotherapeutic drug, and ABT-737, a BCL-2 inhibitor aiming for apoptosis induction, both mediate cytotoxic effect in SCLC cell lines. Experimental results of this research indicate that combination of CI-1040 with etoposide and ABT-737 enhance cell growth inhibition by interfering cell cycle progression and apoptosis promotion. Cross response on PI3K/AKT pathway after drug treatment is also involved in the enforcement. Therefore, MAPK/ERK pathway inhibition may be considered a way to reinforce antitumor ability mediated by therapeutic agents in SCLC treatment.