Abstract
Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, 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.
Highlights
Medicinal plants and their metabolites are great sources for pharmaceutical applications
These results reveal differential sensitivity of these cancer cells to isoplumbagin in terms of survival and invasion
We directly examined how isoplumbagin reduced mitochondrial OXPHOS, the individual OXPHOS complexes′ activity following a substrate uncoupler inhibitor titration (SUIT) protocol [24] that was performed to permeabilized OC3-IV2 cells with digitonin and measured by high-resolution respirometry
Summary
Medicinal plants and their metabolites are great sources for pharmaceutical applications. The metabolites in plants provide a rich variety of bioactive compounds with anticancer, antioxidant, anti-inflammatory, or antimicrobial activities. Some of these drugs such as paclitaxel, docetaxel, resveratrol, vincristine, and vinblastine are approved of and used extensively in treating several types of cancer, including breast, head and neck, testicular, and bladder cancers [1,2]. Quinones are highly electrophilic molecules that accept one- or two-electrons from flavoenzymes and iron-sulfur proteins to form semiquinone or hydroquinone. They exert cytotoxic effects through alkylating proteins or DNA and affect the redox cycle with their semiquinone radicals to generate reactive oxygen species. There is a continued search for the development of quinone-based agents displaying antitumor activity that are less toxic and have reduced side effects
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