Investigating the mechanism of inositol against paclitaxel chemoresistance on triple-negative breast cancer by using 7T multiparametric MRI and mitochondrial changes.

IF 7.4 1区 医学 Q1 Medicine
Wentao Xuan, Wangmin Li, Lixin Ke, Yuanyu Shen, Xiaolei Zhang, Yue Chen, Zhiliang Ye, Caiyu Zhuang, Shiyan Xie, Renhua Wu, Yan Lin
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引用次数: 0

Abstract

Background: 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.

Objective: 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.

Materials and methods: 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.

Results: 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 mm3 vs. 388.98 ± 32.62 mm3, 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).

Conclusion: Inositol may counteract PTX resistance in TNBC by disrupting mitochondrial fission, and DWI combined with DKI effectively tracked this effect.

利用7T多参数MRI和线粒体变化研究肌醇对抗三阴性乳腺癌紫杉醇化疗耐药的机制。
背景:新出现的三阴性乳腺癌(TNBC)治疗靶向线粒体裂变对抗紫杉醇(PTX)耐药性。肌醇对这一过程的抑制使其成为一种潜在的治疗方法。多参数MRI提供了这些创新的早期和有效的评估。目的:利用7T多参数MRI监测肌醇对PTX耐药TNBC小鼠的作用,并结合离体线粒体形态变化进一步探讨肌醇抑制PTX化学耐药的机制。材料和方法:6-8周龄BALB/c小鼠皮下接种PTX耐药4T1细胞,分为PTX处理组(n = 24)、“PTX +肌醇”处理组(n = 24)和未处理组(n = 24)。每组6只小鼠给药后每7 d行弥散加权成像(DWI)和弥散峰度成像(DKI)。采用化学交换饱和转移成像(CEST)观察治疗后肿瘤组织内肌醇的动态变化。每组分别于第0、7、14天处死6只小鼠进行组织病理学检查。在3周的扫描周期后,将各组剩余小鼠安乐死进行组织病理学分析。通过苏木精&伊红(H&E)染色和Ki-67免疫组化评价肌醇的治疗效果。采用Western Blot和电镜观察肌醇对线粒体结构和PTX抗性的影响。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和Spearman秩相关分析。结果:肌醇给药1 h后,肿瘤组织中肌醇CEST信号明显高于给药前(2.75±0.71% vs. 1.80±0.33%,p3 vs. 388.98±32.62 mm3, p)。结论:肌醇可能通过破坏线粒体分裂来对抗TNBC的PTX抵抗,DWI联合DKI有效追踪了这一作用。
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来源期刊
CiteScore
12.00
自引率
0.00%
发文量
76
审稿时长
12 weeks
期刊介绍: Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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