Journal
ONCOLOGY REPORTS
Volume 38, Issue 2, Pages 715-724Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2017.5752
Keywords
breast cancer; apigenin; drug resistance; multidrug resistance 1; signal transducer and activator of transcription 3
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [2015R1C1A2A01051539]
- Traditional Korean Medicine R&D Project of the Ministry of Health and Welfare [HI12C1889, HI13C0530]
- National Research Foundation of Korea [2015R1C1A2A01051539] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-G(0)/G(1) 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-1 alpha 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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