Leung Wai-Hung, Shih Jing-Wen, Chen Jian-Syun, Mokgautsi Ntlotlang, Wei Po-Li, Huang Yan-Jiun
Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan.
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
Biomedicines. 2022 Feb 4;10(2):377. doi: 10.3390/biomedicines10020377.
Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor () oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog () mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in and were associated with some of the top tumorigenic oncogene's overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.
尽管进行了治疗干预，仍有大约25%的结直肠癌（CRC）患者会发展为转移性（m）CRC。在这种情况下，肿瘤细胞会被表皮生长因子受体（）致癌基因所吸引。据报道， Kirsten大鼠肉瘤（RAS）2病毒致癌基因同源物（）突变通过激活Wnt/β-连环蛋白和RAS/细胞外信号调节激酶（ERK）途径促进癌症进展，从而驱动CRC。此外，在几乎40%对mCRC中EGFR抑制剂产生耐药性的患者中也存在 。多项研究表明，癌症干细胞（CSCs）促进肿瘤发生、肿瘤生长和对治疗的耐药性。在CRC中广泛报道的最常见的CSC预后标志物之一是分化簇44（CD44），它调节基质金属蛋白酶7/9（MMP7/9）以促进肿瘤进展和转移；然而，CD44在CRC中的分子作用仍不清楚。在侵袭性CRC中，与正常细胞相比，肿瘤细胞中MMP7的表达被报道过高，并且在CRC西妥昔单抗和奥沙利铂耐药及远处转移中起关键作用。在此，我们利用生物信息学分析，发现与正常组织相比，CRC肿瘤组织中 致癌特征的表达过高。此外， 和 的高突变发生率与一些顶级致癌基因的过表达有关，这最终导致对化疗反应不佳以及对一些FDA批准药物产生耐药性。基于这些发现，我们探索了一种计算方法来对药物柳氮磺胺吡啶进行药物再利用，我们的计算机模拟分子对接显示柳氮磺胺吡啶与 致癌基因有独特的相互作用，与标准抑制剂相比具有更高的结合亲和力。我们的体外分析表明，柳氮磺胺吡啶与顺铂联合使用可降低CRC细胞系中的细胞活力、集落和球体形成。此外，单独使用柳氮磺胺吡啶以及与顺铂联合使用均可抑制DLD-1和HCT116细胞系中 的表达。因此，柳氮磺胺吡啶作为改善CRC患者化疗反应的辅助药物值得进一步研究。
