中草藥 TRM01 之抗非小細胞肺癌研究
No Thumbnail Available
Date
2017
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
癌症一直是世界上致死率最高的疾病，而肺癌更是其中的佼佼者，不論是在 世界上或是台灣，肺癌都是高居十大癌症死因的榜首。根據病理學的型態分類大 致上可以將肺癌分成兩種:非小細胞肺癌(85 %)以及小細胞肺癌(15 %)。在 約 80 %非小細胞肺癌病人身上可以發現表皮細胞生長受體(EGFR)有過度活化 的現象，而導致此現象大多是由於 Exon 19 上的缺失或是 Exon 21 上的 L858R 點突變造成，這些突變會導致細胞癌化並且導致腫瘤的產生以及轉移。在現今的 治療中對非小細胞肺癌的治療主要是手術治療輔以標靶治療，隨著越來越多的小 分子藥物的開發，現在已有開發出表皮細胞生長受體的激酶抑制劑(kinase inhibitor)如 geftinib 以及 erlotinib。但是藥物的使用治療，在臨床上也發現病人 在使用抑制劑之後會在 Exon 20 產生另一個點突變 T790M，而此一突變會導致病 人產生抗藥性以及癌症復發。
科學界近年來一直致力於將中草藥開發應用於治療癌症上，因此本研究希望 可以找到治療非小細胞肺癌的中草藥。本研究從七種中草藥中找到 TRM01 具有 抑制帶有 T790M/L858R 兩種點突變的非小細胞癌細胞株 H1975 生長的中草藥， 也發現 TRM01 可以抑制 EGFR 的表現並能透過 Bcl-2/Caspase-9 訊息傳遞路徑引 起細胞的凋亡(Apoptosis)。另一方面本研究也發現 TRM01 可以透過調控 FAK 的活性來抑制 Rho-family 蛋白的活性以及抑制 EMT 蛋白(N-cadherin、 Fibronectin)的表現來降低 H1975 細胞的遷移(Migration)能力，同時也有發 現 TRM01 具有可以透過調控 AKT/mTOR 訊息傳遞(p-4EBP1、HIF1a)的表現 來抑制癌細胞血管新生的能力。此外本研究藉由動物異種移植(Xenograft)模式，將 H1975 細胞注入小鼠皮下來探討 TRM01 是否可以在活體(In vivo)內抑制腫 瘤生長，結果顯示 TRM01 可以在活體內抑制腫瘤生長。
根據以上的實驗結果，此研究證實 TRM01 具有抑制非小細胞肺癌的血管新 生以及轉移的能力及動物實驗也有抑制腫瘤生長效果，因此在往後的藥物開發以 及腫瘤治療上是具有高度潛力的中草藥物。
Lung cancer is the most common cancer throughout the world and in Taiwan. There are two major forms of lung cancer, which are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Overexpression of epidermal growth factor receptor (EGFR) can be observed in up to 80 % of NSCLC patients that is known to be highly correlated with the in-frame deletion in exon 19 or L858R mutation in exon 21. Accordingly, EGFR tyrosine kinase inhibitors (TKIs) are used to treat NSCLC patients having EGFR mutations. However, the occurrence of acquired resistance to EGFR TKIs leads to the treatment failure, and a secondary mutation (T790M in exon 20) is believed to be an underlying mechanism of resistance. Therefore, it is of urgent need to develop a novel medicine for NSCLC patients, who have the EGFR TKI-resistant. In present study, we identified the most effective Chinese herbal, medicine (CHM) TRM01extracts from seven aqueous of CHM extracts, and TRM01 could selectively inhibit the growth of gefitinib-resistant H1975 cell line harboring EGFR T790M/L858R mutations. The exposure of H1975 cells to TRM01 induced apoptosis mediated by inhibiting EGFR and Bcl-2/Caspase-9 activity. Furthermore, the treatment of TRM01 extracts inhibited H1975 cells migration, through regulating FAK to repress Rho-family protein activities and inhibit EMT protein markers expression. TRM01 also has the inhibitory effects on the angiogenesis of cancer cells by regulating the activity of AKT/mTOR signaling. Furthermore, treatment of TRM01 on xenograft mouse model showed that TRM01 inhibited tumor growth in vivo. Taken together, present study demonstrated that TRM01 inhibited angiogenesis and metastasis of the cell line, H1975 of NSCLC and in vivo, and therefore TRM01 could be developed as a potential cancer treatment for lung cancer.
Lung cancer is the most common cancer throughout the world and in Taiwan. There are two major forms of lung cancer, which are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Overexpression of epidermal growth factor receptor (EGFR) can be observed in up to 80 % of NSCLC patients that is known to be highly correlated with the in-frame deletion in exon 19 or L858R mutation in exon 21. Accordingly, EGFR tyrosine kinase inhibitors (TKIs) are used to treat NSCLC patients having EGFR mutations. However, the occurrence of acquired resistance to EGFR TKIs leads to the treatment failure, and a secondary mutation (T790M in exon 20) is believed to be an underlying mechanism of resistance. Therefore, it is of urgent need to develop a novel medicine for NSCLC patients, who have the EGFR TKI-resistant. In present study, we identified the most effective Chinese herbal, medicine (CHM) TRM01extracts from seven aqueous of CHM extracts, and TRM01 could selectively inhibit the growth of gefitinib-resistant H1975 cell line harboring EGFR T790M/L858R mutations. The exposure of H1975 cells to TRM01 induced apoptosis mediated by inhibiting EGFR and Bcl-2/Caspase-9 activity. Furthermore, the treatment of TRM01 extracts inhibited H1975 cells migration, through regulating FAK to repress Rho-family protein activities and inhibit EMT protein markers expression. TRM01 also has the inhibitory effects on the angiogenesis of cancer cells by regulating the activity of AKT/mTOR signaling. Furthermore, treatment of TRM01 on xenograft mouse model showed that TRM01 inhibited tumor growth in vivo. Taken together, present study demonstrated that TRM01 inhibited angiogenesis and metastasis of the cell line, H1975 of NSCLC and in vivo, and therefore TRM01 could be developed as a potential cancer treatment for lung cancer.
Description
Keywords
非小細胞肺癌, 中草藥, 血管新生, 細胞遷移, 細胞凋亡, 表皮生長因子, non-small cell lung cancer, Chinese herbal medicine, angiogenesis, cell migration, apoptosis, epidermal growth factor