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