Abstract
Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.
Highlights
Breast cancer (BC) is the most common malignant tumor among women in the world, with 2.1 million new patients and 626,679 deaths in 2018 [1]
The results showed that co-treatment with pyrotinib and adriamycin was more effective in SK-BR-3 and AU565 cells
The results showed that pAkt, p-p65, FOXC1 activity were tremendously decreased by pyrotinib treatment at 3, 10mg/ml after 48 h incubation, whereas no significant effect on p-Akt, p-p65, FOXC1 activity was observed in the adriamycin group (Figure 7)
Summary
Breast cancer (BC) is the most common malignant tumor among women in the world, with 2.1 million new patients and 626,679 deaths in 2018 [1]. The overexpression of HER2 or gene amplification accounts for about 15-20% of all BC cases, which is related to the invasiveness of the tumor, and the prognosis is worse without appropriate therapy [2, 3]. Five drugs were approved by the U.S Food and Drug Administration (FDA) for the treatment of HER2positive BC, known as trastuzumab, pertuzumab, TDM-1, lapatinib, and neratinib [6,7,8,9,10]. The Chinese State Drug Administration recently authorized a new tyrosine kinase inhibitor (TKIs), pyrotinib, for the treatment of patients with HER2-positive recurrence and metastasis breast cancer [11]
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