Xuan Wentao, Li Wangmin, Ke Lixin, Shen Yuanyu, Zhang Xiaolei, Chen Yue, Ye Zhiliang, Zhuang Caiyu, Xie Shiyan, Wu Renhua, Lin Yan
Radiology Department, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Breast Cancer Res. 2025 May 28;27(1):93. doi: 10.1186/s13058-025-02051-4.
The emerging triple-negative breast cancer (TNBC) treatments target mitochondrial fission to combat paclitaxel (PTX) resistance. Inositol's inhibition of this process makes it a potential therapy. Multiparametric MRI provides an early and effective assessment of these innovations.
To monitor the efficacy of Inositol on PTX-resistant TNBC mice using 7T multiparametric MRI, and to further explore the mechanism of inositol inhibiting PTX chemoresistance in combination with the morphological changes of isolated mitochondria.
BALB/c mice aged 6-8 weeks were subcutaneously inoculated with PTX-resistant 4T1 cells and divided into three groups: PTX-treated mice (n = 24), "PTX + Inositol"-treated mice (n = 24) and untreated mice (n = 24). Six mice in each group underwent diffused weighted imaging (DWI) and diffusion kurtosis imaging (DKI) every 7 days after administration. To observe the dynamic changes of inositol within the tumor tissue post-treatment, chemical exchange saturation transfer (CEST) imaging was performed. Six mice in each group were sacrificed on day 0, 7, and 14 respectively for histopathological examination. After a 3-week scanning cycle, the remaining mice in each group were euthanized for histopathological analysis. The therapeutic response of inositol was assessed via Hematoxylin & Eosin (H&E) staining and Ki-67 immunohistochemistry. The effects of inositol on mitochondrial structure and PTX resistance were studied by Western Blot and electron microscopy. One-way analysis of variance, independent samples t-test, paired samples t-test, Kruskal-Wallis, and Spearman rank correlation were used.
The CEST signal of inositol in tumor tissue was significantly higher after 1 h of inositol administration than before (2.75 ± 0.71% vs. 1.80 ± 0.33%, p < 0.05). On day 21 after treatment, the tumor volume in the PTX + Ins group was smaller than that in the PTX group (191.52 ± 27.98 mm vs. 388.98 ± 32.62 mm, p < 0.001). The MD, MK, and ADC values were correlated significantly with tumor cell density (MD, r = -0.872; MK, r = 0.723; ADC, r = -0.858) and Ki-67 level (MD, r = -0.975; MK, r = 0.680; ADC, r = -0.860). The p-AMPK levels of PTX + Ins group were lower than that of PTX group (0.50 ± 0.06 vs. 0.60 ± 0.05, p = 0.04), and the mitochondrial length was longer than that of PTX group (0.86 ± 0.10 vs. 0.44 ± 0.09, p < 0.001), with a significant correlation to Ki-67 levels (r = -0.853, p < 0.001).
Inositol may counteract PTX resistance in TNBC by disrupting mitochondrial fission, and DWI combined with DKI effectively tracked this effect.
新兴的三阴性乳腺癌（TNBC）治疗方法旨在通过靶向线粒体裂变来对抗紫杉醇（PTX）耐药性。肌醇对这一过程的抑制作用使其成为一种潜在的治疗方法。多参数磁共振成像（MRI）可对这些创新疗法进行早期有效的评估。
使用7T多参数MRI监测肌醇对PTX耐药TNBC小鼠的疗效，并结合分离线粒体的形态变化进一步探讨肌醇抑制PTX化疗耐药性的机制。
将6 - 8周龄的BALB/c小鼠皮下接种PTX耐药的4T1细胞，并分为三组：PTX治疗组（n = 24）、“PTX + 肌醇”治疗组（n = 24）和未治疗组（n = 24）。给药后，每组每7天对6只小鼠进行扩散加权成像（DWI）和扩散峰度成像（DKI）。为观察治疗后肿瘤组织内肌醇的动态变化，进行化学交换饱和转移（CEST）成像。每组分别在第0天、第7天和第14天处死6只小鼠进行组织病理学检查。经过3周的扫描周期后，每组剩余小鼠安乐死进行组织病理学分析。通过苏木精和伊红（H&E）染色及Ki-67免疫组织化学评估肌醇的治疗反应。通过蛋白质免疫印迹法和电子显微镜研究肌醇对线粒体结构和PTX耐药性的影响。采用单因素方差分析、独立样本t检验、配对样本t检验、Kruskal-Wallis检验和Spearman等级相关性分析。
给予肌醇1小时后，肿瘤组织中肌醇的CEST信号显著高于给药前（2.75±0.71%对1.80±0.33%，p < 0.05）。治疗后第21天，PTX + Ins组的肿瘤体积小于PTX组（191.52±27.98 mm对388.98±32.62 mm，p < 0.001）。表观扩散系数（MD）、平均峰度系数（MK）和扩散系数（ADC）值与肿瘤细胞密度显著相关（MD，r = -0.872；MK，r = 0.
