Abstract

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells with harmine hydrochloride (HMH) to identify its anticancer effects and mechanisms. HMH treatment suppressed cell growth, migration, invasion, and colony formation in MCF-7 and MDA-MB-231 cells, regardless of the hormone signaling. It also reduced the phosphorylation of PI3K, AKT, and mTOR and increased FOXO3a expression. Additionally, HMH treatment increased p38 phosphorylation in MCF-7 cells and activated c-Jun N-terminal kinase (JNK) phosphorylation in MDA-MB-231 cells in a dose-dependent manner, where activated p38 and JNK increased FOXO3a expression. Activated FOXO3a increased the expression of p53, p21, and their downstream proteins, including p-cdc25, p-cdc2, and cyclin B1, to induce G2/M cell cycle arrest. Furthermore, HMH inhibited the PI3K/AKT/mTOR pathway by significantly reducing p-AKT expression in combination with LY294002, an AKT inhibitor. These results indicate that mitogen-activated protein kinases (MAPKs) and AKT/FOXO3a signaling pathways mediate the induction of cell cycle arrest following HMH treatment. Therefore, HMH could be a potential active compound for anticancer bioactivity in BC cells.

Highlights

  • Breast cancer (BC) is one of the most common causes of death in women worldwide and is closely associated with hormones and hormone receptors [1]

  • To determine whether harmine hydrochloride (HMH) was effective in suppressing cell proliferation in human BC cells, MCF-7 and MDA-MB-231 cells were treated with HMH at various concentrations, ranging from 0 to 1000 μM for 24–72 h, and cell proliferation was measured

  • We identified the induction of G2/M cell cycle arrest by HMH in both MCF-7 and MDA-MB-231 BC cells

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Summary

Introduction

Breast cancer (BC) is one of the most common causes of death in women worldwide and is closely associated with hormones and hormone receptors [1]. Triple-negative breast cancer (TNBC), which lacks ER α, progesterone receptors, and HER2, poses a high risk of relapse and metastasis and has a low survival rate after development [2]. The prognosis of patients with BC has improved with treatment, lifestyle modification, early detection, and mastectomy [3], the existing chemotherapeutics have unsatisfactory effectiveness, with some patients showing resistance to chemotherapy drugs [4]. There are complex and diverse risk factors for BC, and the molecular mechanisms underlying pathogenesis have not yet been elucidated. Interest in novel approaches, such as developing new drugs derived from natural products effective in BC treatment with reduced side effects, is increasing [5]

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