19-Hydroxybufalin inhibits non-small cell lung cancer cell proliferation and promotes cell apoptosis via the Wnt/β-catenin pathway

Wei Yu; Xiao Zhang; Wei Zhang; Minggang Xiong; Yuhan Lin; Ming Chang; Lin Xu; Yi Lu; Yun Liu; Jian Zhang

doi:10.1186/s40164-021-00243-0

19-Hydroxybufalin inhibits non-small cell lung cancer cell proliferation and promotes cell apoptosis via the Wnt/β-catenin pathway

Exp Hematol Oncol. 2021 Oct 25;10(1):48. doi: 10.1186/s40164-021-00243-0.

Authors

Wei Yu^{1

2}, Xiao Zhang², Wei Zhang², Minggang Xiong², Yuhan Lin², Ming Chang², Lin Xu¹, Yi Lu^{3

4}, Yun Liu⁵, Jian Zhang^{6

7}

Affiliations

¹ Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment With Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China.
² School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
³ School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China. luy3@sustech.edu.cn.
⁴ Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, 518055, Guangdong, China. luy3@sustech.edu.cn.
⁵ Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment With Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China. liuyunzmu@126.com.
⁶ School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China. zhangjian@sustech.edu.cn.
⁷ Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, 518055, Guangdong, China. zhangjian@sustech.edu.cn.

Abstract

Background: Bufadienolides derived from the skin of toads are often regarded as the main active components with antitumor effects. 19-Hydroxybufalin (19-HB) is a monomer of bufadienolides; however, its effects and underlying molecular mechanisms on tumor growth remain to be ascertained. In this report, we focused on the antitumor effects of 19-HB on non-small cell lung cancer to provide a scientific basis for its further development and utilization.

Methods: The antitumor effects of 19-HB on the human NSCLC cell lines NCI-H1299 and NCI-H838 were examined in vitro. The cells were treated with different concentrations of 19-HB, and the inhibition of cell growth was measured by CCK-8 and colony formation assays. Furthermore, cell apoptosis was analyzed by flow cytometry, TUNEL staining, JC-1 staining, and western blotting. The effects on migration and invasion were evaluated by wound-healing assay, transwell assay, and western blotting. Finally, the antitumor effects of 19-HB were evaluated in vivo using a xenograft mouse model.

Results: 19-HB-treated NSCLC cells showed inhibited cell viability and increased apoptosis. The expression levels of cleaved caspase-3, cleaved-PARP, and Bax/Bcl-2 were upregulated, while the mitochondrial membrane potential decreased. In contrast, migration, invasion, as well as the expression of MMP2, MMP7, MMP9, the epithelial-mesenchymal transition-related proteins N-cadherin and Vimentin, and the transcription factors Snail and Slug were inhibited. Furthermore, the expression levels of the key molecules in the Wnt/β-catenin signaling pathway (CyclinD1, c-Myc, and β-catenin) were decreased. In vivo, the growth of xenograft tumors in nude mice was also significantly inhibited by 19-HB, and there were no significant changes in biochemical indicators of hepatic and renal function.

Conclusions: 19-HB inhibited the proliferation, migration, and invasion, and promoted the apoptosis of NSCLC cells via the Wnt/β-catenin pathway. In addition, 19-HB inhibited the growth of xenograft tumors in nude mice with little toxicity to the liver and kidney. Thus, 19-HB may be a potential antitumor agent for treating NSCLC.

Keywords: 19-Hydroxybufalin; Apoptosis; Migration and invasion; NSCLC.

Abstract

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