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[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models.

ABSTRACT: Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the antitumor and antimetastatic activities of a [6]-gingerol-derived semi-synthetic compound named SSi6 on MDA-MB-231 TNBC cells using xenograft models. SSi6 did not cause toxic effects in vivo as demonstrated by body weight and hematological and histological evaluations. From the orthotopic xenograft model, we demonstrated that SSi6 slows and inhibits the growth of the primary tumor, as well as prevents metastatic spontaneous progression from lymph nodes to the lungs. Moreover, a second xenograft model with resection of the primary tumor showed that SSi6 also blocks the progression of metastases from the lymph nodes to other visceral organs. Taken together, our results demonstrate that SSi6 is a promising compound to be investigated in other preclinical and clinical models to be applied as a complementary therapy for TNBC.

SUBMITTER: Luna-Dulcey L

PROVIDER: S-EPMC8228746 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models.

Luna-Dulcey Liany L Almada da Silva James J Jimenez-Renard Veronica V Caleiras Eduardo E Mouron Silvana S Quintela-Fandino Miguel M Cominetti Marcia R MR

Cancers 20210608 12

Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the antitumor and antimetastatic activities of a [6]-gingerol-derived semi-synthetic compound named SSi6 on MDA-MB-231 TNBC cells using xenograft models. SSi6 did not cause toxic effects <i>in vivo</i> as demonstrated by b ...[more]

PMID: 34201040

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Project description:BackgroundThe triple-negative subtype of breast cancer is particularly challenging to treat due to its aggressiveness with a high risk of brain metastasis, and the lack of effective targeted therapies. Tubulin beta 2B class IIb (TUBB2B), a β-tubulin isoform regulating axon guidance during embryonic development, was found to be overexpressed in various types of cancers including triple-negative breast cancer (TNBC). However, its functional roles in breast cancer or metastasis remain unclear.MethodsTo identify TUBB2B as a novel molecular target in TNBC, we performed bioinformatics analysis to assess the association of TUBB2B expression and survival of patients. RNAscope in situ hybridization was used to examine TUBB2B expression in clinical breast tumor samples. The effect of TUBB2B knockdown on TNBC growth and brain metastasis colonization was evaluated by in vitro and in vivo assays. Mass spectrometry (MS) and biochemical experiments were performed to explore the underlying mechanisms. Preclinical efficacy of targeting TUBB2B was determined in xenograft studies using the siRNA-gold nanoparticle (siRNA-AuNP) approach.ResultsTUBB2B, but not other β-tubulin isoforms, is frequently overexpressed in TNBC primary tumors as well as brain metastases. We also find that upregulation of TUBB2B is associated with poor prognosis in breast cancer patients. Silencing TUBB2B induces tumor cell death and inhibits the outgrowth of brain metastasis. Mechanistically, we identify eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) as a novel interacting partner of TUBB2B, revealing a previously unexplored role of TUBB2B in translational regulation. In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells. These findings suggest a feed-forward interaction between TUBB2B in TNBC cells and astrocytes that promotes brain metastatic colonization. Furthermore, we demonstrate the potent inhibition of TNBC xenograft growth as well as brain metastatic colonization using TUBB2B siRNA-AuNP treatment, indicating potential clinical applications of targeting TUBB2B for TNBC.ConclusionsTUBB2B is a novel TNBC gene that plays a key role in promoting tumor cell survival and brain metastatic colonization, and can be targeted by siRNA-AuNPs as a treatment strategy.

Project description:PurposeAlthough paclitaxel is widely used in cancer treatment, severe side effects and drug resistance limit its clinical use. 10-gingerol (10-G) is a natural compound isolated from ginger, which displays anti-inflammatory, antioxidant, and antiproliferative properties. However, the chemotherapy-sensitization effect of 10-G on triple-negative breast cancer (TNBC) has not been fully clarified. This study is aimed at investigating the effect of 10-G on the paclitaxel sensitivity in TNBC, and its underlying mechanism.MethodsThe study was determined through in vitro and in vivo experiments. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation. To detect cell apoptosis, flow cytometry and TUNEL were used. The expression of proteins was detected by Western blotting and immunohistochemistry. The molecular docking and gene knockout were corroborated by interactions between 10-G and adrenoceptor Beta 2 (ADRB2). The body weight of mice, histopathology and organs (kidney and spleen) coefficients were used to monitor the drug toxicities.ResultsIn vitro, 10-G increased the sensitivity of TNBC cells to paclitaxel, and could synergistically promote the apoptosis of TNBC cells induced by paclitaxel. In combination with molecular docking and lentivirus knockdown studies, ADRB2 was identified as a 10-G binding protein. 10-G inhibited ADRB2 by binding to the active site of ADRB2. Knockdown of ADRB2 reduces the proliferation activity of TNBC cells but also attenuates the sensitizing effects of 10-G to paclitaxel. Western blotting and immunohistochemistry showed that 10-G played an anti-proliferation and chemotherapy-sensitizing role by inhibiting the ADRB2/ERK signal. Toxicity evaluation showed that 10-G would not increase hepatorenal toxicity with paclitaxel.ConclusionThis data suggests that 10-G may be used as a new chemotherapeutic synergist in combination with paclitaxel to enhance anticancer activity. The potential value of ADRB2 as a target for improving chemotherapy sensitivity was also emphasized.

Dataset Information

[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models.

Publications

[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models.

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