Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

Zhao,Hongyan; Zhao,Dali; Jin,Huilin; Li,Hongwei; Yang,Xiaoying; Zhuang,Liwei; Liu,Tiefu

doi:10.3892/mmr.2016.5426

Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

Authors:
- Hongyan Zhao
- Dali Zhao
- Huilin Jin
- Hongwei Li
- Xiaoying Yang
- Liwei Zhuang
- Tiefu Liu
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Affiliations: Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Gastroenterology, The Fourth Hospital of Harbin, Harbin, Heilongjiang 150026, P.R. China
Published online on: June 23, 2016 https://doi.org/10.3892/mmr.2016.5426
Pages: 1817-1822

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Abstract

Cisplatin is the most common chemotherapeutic agent for gastric cancer (GC), however it activates AKT, which contributes to intrinsic and acquired resistance. Bufalin, a traditional Chinese medicine, shows significant anticancer activity by inhibiting the AKT pathway. It was therefore hypothesized that bufalin could counteract cisplatin resistance in GC cells. SGC7901, MKN‑45 and BGC823 human GC cells were cultured under normoxic and hypoxic conditions. Effects of cisplatin and bufalin on GC cells were measured by a cell counting kit, apoptosis was analyzed by flow cytometry, and immunoblotting was used to detect proteins associated with the AKT signaling pathway. It was demonstrated that bufalin synergized with cisplatin to inhibit proliferation and promote apoptosis of GC cells by diminishing the activation of cisplatin-induced AKT under normoxic and hypoxic conditions. Bufalin also inhibits cisplatin-activated molecules downstream of AKT that affect proliferation and apoptosis, including glycogen synthase kinase, mammalian target of rapamycin, ribosomal protein S6 Kinase and eukaryotic translation initiation factor-4E-binding protein-1. To investigate acquired cisplatin resistance, a cisplatin‑resistant cell line SGC7901‑CR was used. It was demonstrated that bufalin reversed acquired cisplatin resistance and significantly induced apoptosis through the AKT pathway. These results imply that bufalin could extend the therapeutic effect of cisplatin on GC cells when administered in combination.

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