Kawiak Anna, Domachowska Anna, Krolicka Aleksandra, Smolarska Monika, Lojkowska Ewa
Department of Biotechnology, Intercollegiate Faculty of Biotechnology UG and MUG, University of Gdansk, Gdansk, Poland.
Front Pharmacol. 2019 Jul 26;10:784. doi: 10.3389/fphar.2019.00784. eCollection 2019.
Resistance acquired toward anti-cancer agents is a significant drawback in breast cancer therapy. A key factor contributing to drug resistance is apoptosis suppression associated with the upregulation of anti-apoptotic Bcl-2 family proteins. Specifically, the anti-apoptotic Mcl-1 protein has been shown to play a significant role in drug resistance, making it an important therapeutic target. The present study aimed at determining the antiproliferative activity of 3-chloroplumbagin (ChPL), a naphthoquinone derived from a sp., toward breast cancer cells and examining the involvement of Mcl-1 inhibition in ChPL-induced cell death. The results showed that ChPL inhibited breast cancer cell proliferation and induced apoptosis through the intrinsic pathway through down-regulation of anti-apoptotic Bcl-2 family proteins. The induction of apoptosis by ChPL was found to be mediated through MAP kinase signaling inhibition. ChPL inhibited the phosphorylation of MEK and ERK proteins in breast cancer cells, and increased apoptosis induction in cells with reduced ERK expression. Furthermore, ERK silencing decreased the expression of Mcl-1 in ChPL-treated cells. The results of this research indicate that ChPL induces apoptosis in breast cancer cells through MAPK-mediated Mcl-1 inhibition, suggesting further research into its potential in breast cancer treatment.
对抗癌药物产生耐药性是乳腺癌治疗中的一个重大缺陷。导致耐药性的一个关键因素是与抗凋亡Bcl-2家族蛋白上调相关的细胞凋亡抑制。具体而言，抗凋亡蛋白Mcl-1已被证明在耐药性中起重要作用，使其成为一个重要的治疗靶点。本研究旨在确定3-氯石蒜醌（ChPL）（一种从 属植物中提取的萘醌）对乳腺癌细胞的抗增殖活性，并研究抑制Mcl-1在ChPL诱导的细胞死亡中的作用。结果表明，ChPL通过下调抗凋亡Bcl-2家族蛋白，抑制乳腺癌细胞增殖并通过内源性途径诱导细胞凋亡。发现ChPL诱导的细胞凋亡是通过抑制MAP激酶信号传导介导的。ChPL抑制乳腺癌细胞中MEK和ERK蛋白的磷酸化，并增加ERK表达降低的细胞中的细胞凋亡诱导。此外，ERK沉默降低了ChPL处理细胞中Mcl-1的表达。本研究结果表明，ChPL通过MAPK介导的Mcl-1抑制诱导乳腺癌细胞凋亡，提示对其在乳腺癌治疗中的潜力进行进一步研究。
