開發複合型藥物應用在表皮生長因子受體突變之非小細胞肺癌

Abstract

腫瘤學家在癌症的治療迄今仍面臨許多嚴峻的挑戰，特別是療程中先天及後天抗藥性。這種困境在具有表皮生長因子受體 (EGFR) 突變及活化的癌細胞中特別嚴重。因此針對EGFR突變的抗藥性去發展新的藥物為當前癌症研究中的重要問題之一。目前的研究中發現可同時干擾多個目標蛋白的藥物其效果會較單一目標的藥物高，而中草藥成為主要為設計多目標標的 (multi-target) 生物活性藥物之重要來源。合併用藥為一種被廣泛使用於設計多目標標的之方法，並應用於多種複雜型的疾病，包括癌症。因此，本研究使用九種中草藥(黃芩、白花蛇舌草、桔梗、魚腥草、半枝蓮、半夏、丹參、厚朴、貝母)，為常使用於非小細胞肺癌(NSCLC)患者治療之藥物。研究中利用直交實驗設計(OED)方法合併成不同濃度的中草藥複方，再分別以不同細胞株篩選藥物，包括正常肺細胞株 (BEAS-2B)、未突變EGFR細胞株 (NCI-H292)、EFGR突變細胞株 (HCC827) 和 EGFR 雙突變細胞株 (NCI-H1975)。進一步分析所有中草藥實驗組合，選出最佳濃度組合，此組合能使正常細胞株存活率高而三株癌細胞存活率低。並分析證明複合藥物作用機制主要藉由誘發癌細胞走向細胞凋亡。本研究成功篩選出最佳組合濃度的複合藥深具潛力能有效克服對具有EGFR突變及雙突變之NSCLC患者治療之抗藥性。

Oncologists are facing formidable challenges in overcoming cancers with either innate or acquired resistance to cancer therapies, especially for the cancers with EGFR mutation and activation. Therefore, the development of new drugs against drug resistance of the EGFR-mutation cancer is one of the major cancer researches. There is a general agreement that multiple-target molecules might be more effective than single-target agents. Chinese herbal medicines are becoming important resources for designing multi-target bioactive molecules. Combination therapy is one of the well-studied multiple-target approaches, gradually used to treat various types of diseases, including cancers. Hence, this work investigates nine Chinese herbal medicines (Herba Hedyotidis, Radix Platycodonis, Herba Houttuyniae, Herba Scutellariae barbatae, Rhizoma Pinelliae preparata, Radix Scutriae, Rellaadix Salviae miltiorrhizae, Cortex Magnoliae officinalis, and Bulbus Fritillariae thunbergii). These herbs are frequently used in the herbal medication to treat non-small cell lung cancer (NSCLC) patients. Afterwards, these nine Chinese herbal medicines are combined and then treated in normal lung cell line (BEAS-2B), EGFR wild type cell line (NCI-H292), EFGR mutation (HCC827) and double mutation cell lines (NCI-H1975). The drug dose and combination are determined based on an orthogonal experimental design method. The objective of the combined Chinese herbal medicine is to minimize the number of cancel cells survived and to maximize the number of normal cells survived. Consequently, the mechanism of the combination drug via cell apoptosis induction is further validated. This work purposes a combination drug with optimized dosage that is potentially effective to copes with the drug resistance to the EGFR-mutation therapy for NSCLC patients.