The naturally occurring flavonoid nobiletin reverses methotrexate resistance via inhibition of P-glycoprotein synthesis |
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Authors: | Rui Liu Yurong Song Chenxi Li Zhengjia Zhang Zeyu Xue Qingcai Huang Liuchunyang Yu Dongjie Zhu Zhiwen Cao Aiping Lu Cheng Lu Yuanyan Liu |
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Affiliation: | 1.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China;2.School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, China;3.Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China |
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Abstract: | Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp–mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp–induced drug efflux. |
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Keywords: | methotrexate-induced drug resistance, rheumatoid arthritis, nobiletin, P-glycoprotein, PI3K/AKT/HIF-1α , glycolysis |
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