Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, 15 Jinju-daero 816 Beon-gil, Jinju 52727, Republic of Korea.
Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea.
Int J Mol Sci. 2023 Jun 7;24(12):9867. doi: 10.3390/ijms24129867.
β-lapachone (β-Lap), a topoisomerase inhibitor, is a naturally occurring -naphthoquinone phytochemical and is involved in drug resistance mechanisms. Oxaliplatin (OxPt) is a commonly used chemotherapeutic drug for metastatic colorectal cancer, and OxPt-induced drug resistance remains to be solved to increase chances of successful therapy. To reveal the novel role of β-Lap associated with OxPt resistance, 5 μM OxPt-resistant HCT116 cells (HCT116-OxPt-R) were generated and characterized via hematoxylin staining, a CCK-8 assay and Western blot analysis. HCT116-OxPt-R cells were shown to have OxPt-specific resistance, increased aggresomes, upregulated p53 and downregulated caspase-9 and XIAP. Through signaling explorer antibody array, nucleophosmin (NPM), CD37, Nkx-2.5, SOD1, H2B, calreticulin, p38 MAPK, caspase-2, cadherin-9, MMP23B, ACOT2, Lys-acetylated proteins, COL3A1, TrkA, MPS-1, CD44, ITGA5, claudin-3, parkin and ACTG2 were identified as OxPt-R-related proteins due to a more than two-fold alteration in protein status. Gene ontology analysis suggested that TrkA, Nkx-2.5 and SOD1 were related to certain aggresomes produced in HCT116-OxPt-R cells. Moreover, β-Lap exerted more cytotoxicity and morphological changes in HCT116-OxPt-R cells than in HCT116 cells through the downregulation of p53, Lys-acetylated proteins, TrkA, p38 MAPK, SOD1, caspase-2, CD44 and NPM. Our results indicate that β-Lap could be used as an alternative drug to overcome the upregulated p53-containing OxPt-R caused by various OxPt-containing chemotherapies.
β-拉帕醌（β-Lap）是一种拓扑异构酶抑制剂，是一种天然存在的萘醌植物化学物质，参与耐药机制。奥沙利铂（OxPt）是转移性结直肠癌常用的化疗药物，增加成功治疗的机会仍然需要解决 OxPt 诱导的耐药性问题。为了揭示与 OxPt 耐药相关的 β-Lap 的新作用，生成并通过苏木精染色、CCK-8 测定和 Western blot 分析对 5 μM OxPt 耐药 HCT116 细胞（HCT116-OxPt-R）进行了表征。结果表明，HCT116-OxPt-R 细胞具有 OxPt 特异性耐药性，聚集物增加，p53 上调，caspase-9 和 XIAP 下调。通过信号转导探索者抗体阵列，核磷蛋白（NPM）、CD37、Nkx-2.5、SOD1、H2B、钙网蛋白、p38 MAPK、caspase-2、钙粘蛋白-9、MMP23B、ACOT2、Lys-乙酰化蛋白、COL3A1、TrkA、MPS-1、CD44、ITGA5、claudin-3、parkin 和 ACTG2 由于蛋白质状态改变超过两倍而被鉴定为 OxPt-R 相关蛋白。基因本体论分析表明，TrkA、Nkx-2.5 和 SOD1 与 HCT116-OxPt-R 细胞中产生的某些聚集物有关。此外，β-Lap 通过下调 p53、Lys-乙酰化蛋白、TrkA、p38 MAPK、SOD1、caspase-2、CD44 和 NPM，在 HCT116-OxPt-R 细胞中的细胞毒性和形态变化比 HCT116 细胞中更为明显。我们的结果表明，β-Lap 可用作克服各种含有 OxPt 的化疗药物引起的上调的包含 p53 的 OxPt-R 的替代药物。
