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Inhibitory Effects of Multivalent Polypeptides on the Proliferation and Metastasis of Breast Cancer Cells.

ABSTRACT: The susceptibility of peptide drugs to enzymatic degradation has limited their clinical applications. To overcome this limitation, we attached the peptide tyroserleutide (YSL) to a molecular scaffold in order to produce homogeneous monovalent, bivalent, tetravalent, and octavalent YSL dendrimers with highly ordered secondary structures. These multivalent YSL dendrimers were resistant to proteolysis and were better able to induce cytotoxicity in tumor cells in vitro as compared with monomeric peptides. These multivalent YSL dendrimers were also better able to constrain tumor cell metastasis. Compared with monovalent YSL, the multivalent YSL dendrimers displayed enhanced in vivo antitumor activity and suppressed tumor growth and metastasis in BALB/c mice bearing 4T1 tumors. These findings indicate that multivalence can significantly enhance ligand potency and represent a potential method for the development of peptide drugs with high therapeutic potential.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6912875 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Inhibitory Effects of Multivalent Polypeptides on the Proliferation and Metastasis of Breast Cancer Cells.

Zhang Zhuangzhuang Z Li Yachao Y Wu Huayu H Zhang Xiao X Zhong Dan D Wu Yahui Y Xu Xianghui X Yang Jun J Gu Zhongwei Z

ACS medicinal chemistry letters 20191111 12

The susceptibility of peptide drugs to enzymatic degradation has limited their clinical applications. To overcome this limitation, we attached the peptide tyroserleutide (YSL) to a molecular scaffold in order to produce homogeneous monovalent, bivalent, tetravalent, and octavalent YSL dendrimers with highly ordered secondary structures. These multivalent YSL dendrimers were resistant to proteolysis and were better able to induce cytotoxicity in tumor cells <i>in vitro</i> as compared with monome ...[more]

PMID: 31857837

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Project description:Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.

Dataset Information

Inhibitory Effects of Multivalent Polypeptides on the Proliferation and Metastasis of Breast Cancer Cells.

Publications

Inhibitory Effects of Multivalent Polypeptides on the Proliferation and Metastasis of Breast Cancer Cells.

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