Low-intensity pulsed ultrasound combined with microbubble mediated JNK/c-Jun pathway to reverse multidrug resistance in triple-negative breast cancer

被引：0
作者：
Nina Qu [1 ]
Zhihui Wu [2 ]
Qingkai Meng [3 ]
Menglu Bi [3 ]
Hexiu Liu [4 ]
Xiaoli Cao [1 ]
Yanqing Liu [5 ]
机构：
[1] Department of Ultrasound Medicine, Yantai Yuhuangding Hospital, Yantai
[2] Department of Vascular Ultrasound, Xiongan Xuanwu Hospital, Xiongan New Area
[3] School of Medical Imaging, Binzhou Medical University, Yantai
[4] School of Medical Imaging, Weifang Medical University, Weifang
[5] Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai
来源：
Scientific Reports | / 14卷 / 1期
关键词：
Doxorubicin; JNK/c-Jun signaling pathway; Low-intensity pulse ultrasound; Microbubbles; Multidrug resistance; Triple-negative breast cancer;
D O I：
10.1038/s41598-024-78272-y
中图分类号：
学科分类号：
摘要：
To investigate the effects of low-intensity pulsed ultrasound combined with microbubble (LIPUS-MB) mediated JNK/c-Jun pathway reversal on multidrug resistance in triple-negative breast cancer and the underlying mechanisms. An orthogonal experiment was designed to screen for the optimal parameters of LIPUS-MB in MDA-MB-231/DOX cells. The CCK-8 assay was used to determine the drug resistance of the cells and to measure their proliferation activity and resistance reversal efficiency at the optimal parameters. Hoechst 33,342 staining and Annexin V-FITC/PI staining were employed to detect cell morphological changes and apoptosis, respectively. The MDA-MB-231/DOX models of transplanted tumor were established in BALB/c. The impact of LIPUS-MB on allograft tumor growth was observed in vivo. Immunohistochemistry was employed to investigate the expression of P-gp, ABCG2, and Ki-67 in tumor tissues, while western blot was utilized to assess the protein expression of P-gp, ABCG2, JNK, p-JNK, c-Jun, p-c-Jun, Bcl-2 and Bax in both MDA-MB-231/DOX cells and allograft tumor tissues. The optimal LIPUS-MB parameters for MDA-MB-231/DOX cells are the microbubble concentration of 20%, ultrasound intensity of 1.0 W/cm2, and irradiation time of 60 s. The drug resistance index of MDA-MB-231/DOX cells is 19.17. Following the optimal parameter application, the IC50 value of the cells decreases by 5.71-fold, with a reversal efficiency of 87.03%, and a simultaneous decrease in cell proliferation activity. Compared with other groups, the DOX + LIPUS-MB group displayed the highest incidence of apoptotic nuclear morphology, and the greatest quantity of cellular apoptosis and the most pronounced decrease in the expression levels of P-gp, ABCG2, p-JNK, p-c-Jun, and Bcl-2 proteins within the cells. Conversely, the expression levels of Bax proteins reach the highest levels (all P < 0.05). Furthermore, in vivo subcutaneous tumor transplantation experiments in nude mice revealed that the DOX + LIPUS-MB group exhibited smaller tumor growth rate, volume and the expression of P-gp, ABCG2, and Ki-67 compared to the DOX + LIPUS group, indicating the most pronounced inhibitory effect on tumor growth and it significantly inhibited tumor proliferation, promoted its apoptosis. In conclusion, following parameter optimization, LIPUS-MB was found to reduce the drug resistance of MDA-MB-231/DOX cells. The underlying mechanism may involve the downregulation of P-gp and ABCG2 proteins expression through the modulation of the JNK/c-Jun pathway by LIPUS-MB, thereby inhibiting cell proliferation activity and promoting apoptosis, and enhancing the in vivo anti-tumor effect of DOX, thus reversing multidrug resistance in triple-negative breast cancer. © The Author(s) 2024.
引用
收藏
相关论文
共 35 条
  • [21] Wang M., Et al., Sonoporation-induced cell membrane permeabilization and cytoskeleton disassembly at varied acoustic and microbubble-cell parameters, Sci. Rep, 8, 1, (2018)
  • [22] Yang Y., Li Q., Guo X., Tu J., Zhang D., Mechanisms underlying sonoporation: Interaction between microbubbles and cells, Ultrason. Sonochem, 67, (2020)
  • [23] Qu N., Et al., Breast Cancer cell line phenotype affects Sonoporation Efficiency under Optimal Ultrasound Microbubble conditions, Med. Sci. Monitor: Int. Med. J. Experimental Clin. Res, 24, pp. 9054-9062, (2018)
  • [24] Qiu F., Chen J., Cao J., Diao F., Huang P., Lowintensity lowfrequency ultrasound enhances the chemosensitivity of gemcitabineresistant ASPC-1 cells via PI3K/AKT/NFκB pathwaymediated ABC transporters, Oncol. Rep, 44, 3, pp. 1158-1168, (2020)
  • [25] Zhu M.M., Et al., Increased JNK1 signaling pathway is responsible for ABCG2-mediated multidrug resistance in human colon cancer, PloS One, 7, 8, (2012)
  • [26] Liu X.Y., Liu S.P., Jiang J., Zhang X., Zhang T., Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein, Eur. Rev. Med. Pharmacol. Sci, 20, 6, pp. 1098-1108, (2016)
  • [27] Alatrash G., Jakher H., Stafford P.D., Mittendorf E.A., Cancer immunotherapies, their safety and toxicity, Exp. Opin. Drug Saf, 12, 5, pp. 631-645, (2013)
  • [28] Wu Q., Et al., Selective inhibitors for JNK signalling: a potential targeted therapy in cancer, J. Enzyme Inhib. Med. Chem, 35, 1, pp. 574-583, (2020)
  • [29] Wang P.P., Et al., Astragaloside IV downregulates the expression of MDR1 in Bel-7402/FU human hepatic cancer cells by inhibiting the JNK/cJun/AP-1 signaling pathway, Mol. Med. Rep, 16, 3, pp. 2761-2766, (2017)
  • [30] Huang Y.C., Pan W., Li H., Yan T., c-Jun NH2-terminal kinase suppression significantly inhibits the growth of transplanted breast tumors in mice, J. Int. Med. Res, 48, 6, (2020)
1234