Dataset Information

Preparation, Characterization, and Inhibition of Hyaluronic Acid Oligosaccharides in Triple-Negative Breast Cancer.

ABSTRACT: Hyaluronic acid (hyaluronan, HA) is a critical component of the extracellular matrix and plays an important biological function of interacting with different molecules and receptors. In this study, both odd- and even-numbered HA oligosaccharides (HAOs) with specific degrees of polymerization (DP) were prepared by different hydrochloric acid hydrolyses, and their structures were characterized by means of HPLC, ESI-MS, and NMR. The data show that the odd-numbered HAOs (DP3-11) have a glucuronic acid reducing end, while the even-numbered HAOs (DP2-10) have an N-acetylglucosamine reducing end. Biological evaluations indicated that all HAOs significantly inhibited the growth and migration of triple-negative breast cancer (TNBC) MDA-MB-231 cells. Among these oligosaccharides, the HA tetrasaccharide (DP4) was confirmed to be the minimum fragment necessary to inhibit MDA-MB-231 cells. Our data suggest that HAOs have potential value in the treatment of TNBC.

SUBMITTER: Han W

PROVIDER: S-EPMC6770828 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Preparation, Characterization, and Inhibition of Hyaluronic Acid Oligosaccharides in Triple-Negative Breast Cancer.

Han Wenwei W Song Lili L Wang Yingdi Y Lv Youjing Y Chen Xiangyan X Zhao Xia X

Biomolecules 20190901 9

Hyaluronic acid (hyaluronan, HA) is a critical component of the extracellular matrix and plays an important biological function of interacting with different molecules and receptors. In this study, both odd- and even-numbered HA oligosaccharides (HAOs) with specific degrees of polymerization (DP) were prepared by different hydrochloric acid hydrolyses, and their structures were characterized by means of HPLC, ESI-MS, and NMR. The data show that the odd-numbered HAOs (DP3-11) have a glucuronic ac ...[more]

PMID: 31480599

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Project description:Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

Project description:Triple-negative breast cancer (TNBC) comprises ∼20% of all breast cancers and is the most aggressive mammary cancer subtype. Devoid of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2), that define most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies. Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA), were investigated in multiple preclinical models of TNBC. NO2-OA reduced TNBC cell growth and viability in vitro, attenuated TNFα-induced TNBC cell migration and invasion, and inhibited the tumor growth of MDA-MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The up-regulation of these aggressive tumor cell growth, migration, and invasion phenotypes is mediated in part by the constitutive activation of pro-inflammatory nuclear factor κB (NF-κB) signaling in TNBC. NO2-OA inhibited TNFα-induced NF-κB transcriptional activity in human TNBC cells and suppressed downstream NF-κB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 and urokinase-type plasminogen activator. The mechanisms accounting for NF-κB signaling inhibition by NO2-OA in TNBC cells were multifaceted, as NO2-OA (a) inhibited the inhibitor of NF-κB subunit kinase β phosphorylation and downstream inhibitor of NF-κB degradation, (b) alkylated the NF-κB RelA protein to prevent DNA binding, and (c) promoted RelA polyubiquitination and proteasomal degradation. Comparisons with non-tumorigenic human breast epithelial MCF-10A and MCF7 cells revealed that NO2-OA more selectively inhibited TNBC function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, including a more favorable thiol/disulfide balance, greater extents of multidrug resistance protein-1 (MRP1) expression, and greater MRP1-mediated efflux of NO2-OA-glutathione conjugates. These observations reveal that electrophilic fatty acid nitroalkenes react with more alkylation-sensitive targets in TNBC cells to inhibit growth and viability.

Dataset Information

Preparation, Characterization, and Inhibition of Hyaluronic Acid Oligosaccharides in Triple-Negative Breast Cancer.

Publications

Preparation, Characterization, and Inhibition of Hyaluronic Acid Oligosaccharides in Triple-Negative Breast Cancer.

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