Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells

Seo,Hye‑Sook; Ku,Jin Mo; Choi,Hyeong Sim; Woo,Jong‑Kyu; Lee,Byung Hoon; Kim,Doh Sun; Song,Hyun Jong; Jang,Bo‑Hyoung; Shin,Yong Cheol; Ko,Seong‑Gyu

doi:10.3892/or.2017.5752

Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells

Authors:
- Hye‑Sook Seo
- Jin Mo Ku
- Hyeong Sim Choi
- Jong‑Kyu Woo
- Byung Hoon Lee
- Doh Sun Kim
- Hyun Jong Song
- Bo‑Hyoung Jang
- Yong Cheol Shin
- Seong‑Gyu Ko
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Affiliations: Laboratory of Clinical Biology and Pharmacogenomics and Center for Clinical Research and Genomics, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Dongdaemun‑gu, Seoul 02447, Republic of Korea, College of Veterinary Medicine, Seoul National University, Gwanak‑gu, Seoul 08826, Republic of Korea, Department of Applied Korean Medicine, Graduate School, Kyung Hee University, Dongdaemun‑gu, Seoul 02447, Republic of Korea
Published online on: June 26, 2017 https://doi.org/10.3892/or.2017.5752
Pages: 715-724
Copyright: © Seo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Drug resistance in chemotherapy is a serious obstacle for the successful treatment of cancer. Drug resistance is caused by various factors, including the overexpression of P‑glycoprotein (P‑gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin‑resistant breast cancer cells (MCF‑7/ADR). In our experiments, apigenin significantly decreased cell growth and colony formation in MCF‑7/ADR cells and parental MCF‑7 cells. This growth inhibition was related to the accumulation of cells in the sub‑G0/G1 apoptotic population and an increase in the number of apoptotic cells. Apigenin reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance‑associated proteins (MRPs) in MCF‑7/ADR cells. Apigenin also downregulated the expression of P‑gp. Apigenin reversed drug efflux from MCF‑7/ADR cells, resulting in rhodamine 123 (Rho123) accumulation. Inhibition of drug resistance by apigenin is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Apigenin decreased STAT3 activation (p‑STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP‑9, which are STAT3 target genes. A STAT3 inhibitor, JAK inhibitor I and an HIF‑1α inhibitor decreased cell growth in MCF‑7 and MCF‑7/ADR cells. Taken together, these results demonstrate that apigenin can overcome drug resistance.

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