藉由解剖學治療學及化學分類系統與同源藥理揭露非癌症藥物於癌症治療

Abstract

癌症為台灣十大死因之首。目前雖然已有許多癌症藥物與治療方法被提出，但大部分的癌症藥物卻常因癌症轉移與抗藥性的問題而效果不彰。因此發展新的癌症藥物是當務之急。近幾年來，舊藥新用被認為有助於加快藥物發展的進程。在我們先前研究中，我們提出一嶄新的「同源藥理」概念，來描述一群相似的藥物與標靶蛋白間的保留性結合環境與特性。藉由保留的交互作用與物化特性，藥物可以結合同屬一同源藥理分群中的蛋白質。 在此論文中，我們應用「同源藥理」概念來尋找可能用於治療癌症的非癌症藥物，我們也成功找到兩類非癌症用藥的新用途。第一類原用於治療阿茲海默症的神經用藥，我們發現其可抑制乳癌腫瘤的轉移。同源藥理辨別出可能的標靶為尼古丁乙烯膽鹼受體(CHRNAs)，先前研究已指出CHRNA7與CHRNA9可能為潛力乳癌的標靶蛋白。結果顯示尼古丁乙烯膽鹼受體有兩可能的結合位置，為尼古丁結合位與異位結合位。結合在異位結合位的藥物會影響乙烯膽鹼結合，進而抑制蛋白質功能。進一步，我們挑選三個藥物進行乳癌細胞(MDA-MB-231)與動物測試。實驗結果顯示，異位結合位的藥物可有效抑制乳癌腫瘤轉移。其中原用於治療阿茲海默症的藥物可抑制70%的乳癌細胞(MDA-MB-231)侵襲能力。抗憂鬱症藥物在動物實驗中也有效抑制腫瘤轉移。我們也發現第二類藥物，口服避孕藥(ethynodiol diacetate)，能用於治療EGFR突變型肺癌。我們結果顯示ethynodiol diacetate能結合在肺癌中高表現的androgen receptor。此避孕藥測試在肺癌細胞株的IC50為55.9 M。我們相信透過「同源藥理」概念，將可幫助新藥開發與舊藥新用。

Cancer is the leading cause of deaths in Taiwan. Many cancer drugs and therapies were proposed; however, most of cancer drugs are unable to work effectively due to cancer metastasis and drug resistance. Therefore, drug development of new cancer therapy is urgently needed. Recently, drug repurposing is a great solution for enhancing the efficiency of drug development. In our previous studies, we proposed the novel concept “Homopharma" to describe the conserved binding environment and preferred properties between a set of similar drugs and similar targets. These drugs can often bind to the targets based on the conserved interactions and similar physico-chemical properties. In this thesis, we applied Homopharma to identify drug repurposing for cancer treatment by existing non-cancer drugs and successfully identified new indications of two kinds of non-cancer drugs. First, the CNS drugs, which are original used for Alzheimer's disease and depression, was identified to treat for metastasis of breast cancer. Five homopharma groups were recognized by the nicotinic acetylcholine receptors (CHRNAs). The CHRNA7 and CHRNA9 are potential targets for advanced breast cancer. Our results showed that there are two potential binding sites of CHRNAs, including the nicotine binding site and the allosteric site. The drug binding on the allosteric site may inhibit CHRNA by disturbing binding of nicotinic acetylcholine. Furthermore, we selected three non-cancer drugs from different homopharma groups and tested them on advanced breast cancer cell line, MDA-MB-231. The experimental results showed that the drugs on the allosteric site can inhibit the cancer metastasis. The antidepressant and the drug for Alzheimer's disease reduce over 70% invasion rate of MDA-MB-231. Furthermore, the antidepressant is much more effective on animal model. Second, the ethynodiol diacetate, using for acne or contraceptive, was discovered for EGFR-mutant lung cancer based on homopharma groups. Our results indicated that ethynodiol diacetate can bind androgen receptor (AR), which is overexpressed on lung cancer. This contraceptive was tested using lung cancer cell assay. The IC50 is 55.9 M. We believe that the concept of homopharma is advantageous for drug development and drug repurposing.