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Abstract：
Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC.
摘要：
已显示细胞色素P450（CYP450）酶在结直肠癌（CRC）中表达，其失调与肿瘤进展和不良预后有关。在这里，我们研究了在CRC中使用洛匹那韦/利托那韦靶向CYP450的治疗潜力。利用综合系统生物学方法和RNAseq研究与结直肠癌患者相关基因的差异水平。在单层和三维（3D）模型中评估了洛匹那韦/利托那韦的抗增殖活性，然后是伤口愈合试验。在小鼠模型中检查靶向CYP450的有效性，然后进行组织病理学分析,生化试验(MDA，SOD,硫醇和CAT），和RT-PCR。失调表达基因（DEG）的数据揭示了CRC中1268个上调基因和1074个下调基因。在得分最高的基因和失调的途径中，检测到CYPs并与CRC患者的不良预后相关。抑制CYP450通过调节survivin降低细胞增殖，Chop,CYP13a,和诱导细胞死亡，如通过AnnexinV/PI染色检测。该试剂通过诱导E-钙粘蛋白抑制细胞的迁移行为。此外，洛匹那韦/利托那韦抑制肿瘤生长和纤维化，与SOD/硫醇水平降低和MDA水平升高相关。我们的研究结果表明，在结直肠癌中使用洛匹那韦/利托那韦靶向CYP450的治疗潜力，支持对这种新的CRC治疗方法的未来研究。
