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

共 35 条

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