Beklen Hande, Gulfidan Gizem, Arga Kazim Yalcin, Mardinoglu Adil, Turanli Beste
Department of Bioengineering, Marmara University, Istanbul, Turkey.
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.
Front Oncol. 2020 Aug 13;10:1273. doi: 10.3389/fonc.2020.01273. eCollection 2020.
Colorectal cancer (CRC) is one of the most fatal types of cancers that is seen in both men and women. CRC is the third most common type of cancer worldwide. Over the years, several drugs are developed for the treatment of CRC; however, patients with advanced CRC can be resistant to some drugs. P-glycoprotein (P-gp) (also known as Multidrug Resistance 1, MDR1) is a well-identified membrane transporter protein expressed by ABCB1 gene. The high expression of MDR1 protein found in several cancer types causes chemotherapy failure owing to efflux drug molecules out of the cancer cell, decreases the drug concentration, and causes drug resistance. As same as other cancers, drug-resistant CRC is one of the major obstacles for effective therapy and novel therapeutic strategies are urgently needed. Network-based approaches can be used to determine specific biomarkers, potential drug targets, or repurposing approved drugs in drug-resistant cancers. Drug repositioning is the approach for using existing drugs for a new therapeutic purpose; it is a highly efficient and low-cost process. To improve current understanding of the MDR-1-related drug resistance in CRC, we explored gene co-expression networks around ABCB1 gene with different network sizes (50, 100, 150, 200 edges) and repurposed candidate drugs targeting the ABCB1 gene and its co-expression network by using drug repositioning approach for the treatment of CRC. The candidate drugs were also assessed by using molecular docking for determining the potential of physical interactions between the drug and MDR1 protein as a drug target. We also evaluated these four networks whether they are diagnostic or prognostic features in CRC besides biological function determined by functional enrichment analysis. Lastly, differentially expressed genes of drug-resistant (i.e., oxaliplatin, methotrexate, SN38) HT29 cell lines were found and used for repurposing drugs with reversal gene expressions. As a result, it is shown that all networks exhibited high diagnostic and prognostic performance besides the identification of various drug candidates for drug-resistant patients with CRC. All these results can shed light on the development of effective diagnosis, prognosis, and treatment strategies for drug resistance in CRC.
结直肠癌（CRC）是男性和女性中最致命的癌症类型之一。CRC是全球第三大常见癌症类型。多年来，已开发出几种用于治疗CRC的药物；然而，晚期CRC患者可能对某些药物产生耐药性。P-糖蛋白（P-gp）（也称为多药耐药1，MDR1）是一种由ABCB1基因表达的已明确的膜转运蛋白。在几种癌症类型中发现的MDR1蛋白的高表达会导致化疗失败，因为药物分子会从癌细胞中流出，降低药物浓度，并导致耐药性。与其他癌症一样，耐药性CRC是有效治疗的主要障碍之一，迫切需要新的治疗策略。基于网络的方法可用于确定耐药性癌症中的特定生物标志物、潜在药物靶点或重新利用已批准的药物。药物重新定位是将现有药物用于新治疗目的的方法；这是一个高效且低成本的过程。为了提高目前对CRC中MDR-1相关耐药性的理解，我们探索了围绕ABCB1基因的不同网络规模（50、100、150、200条边）的基因共表达网络，并通过使用药物重新定位方法重新利用靶向ABCB1基因及其共表达网络的候选药物来治疗CRC。还通过分子对接评估候选药物，以确定药物与作为药物靶点的MDR1蛋白之间物理相互作用的潜力。除了通过功能富集分析确定的生物学功能外，我们还评估了这四个网络是否是CRC的诊断或预后特征。最后，发现了耐药（即奥沙利铂、甲氨蝶呤、SN38）HT29细胞系的差异表达基因，并用于重新利用具有逆转基因表达的药物。结果表明，除了为耐药性CRC患者鉴定各种候选药物外，所有网络都表现出高诊断和预后性能。所有这些结果可为CRC耐药性的有效诊断、预后和治疗策略的开发提供启示。
