Discovery of Isoplumbagin as a Novel NQO1 Substrate and Anti-Cancer Quinone

• Main Authors: Yen-Chi Tsao, Yu-Jung Chang, Chun-Hsien Wang, Linyi Chen
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: International Journal of Molecular Sciences
• Subjects: isoplumbagin; NQO1; quinone; cancer; metastasis
• Online Access: https://www.mdpi.com/1422-0067/21/12/4378

Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from <i>Lawsonia inermis</i> and <i>Plumbago europaea</i>, has been reported to have anti-inflammatory and antimicrobial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anticancer effect of chemically synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer HeLa cells by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Boyden chamber assays. In vivo studies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] dehydrogenase quinone 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity, and thus compromises mitochondrial function. Collectively, this work reveals an anticancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function.