Abstract
We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol α and human pol γ. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol α, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50 = 2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol α inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin.
Highlights
Cancer is a major global public health problem
We focused on 5-hydroxy-2-methyl-1,4-naphthoquinone, which has the common naphthoquinone skeleton and a hydroxyl group and a methyl group at the C-5 and C-2 positions, respectively
We previously found that a vitamin K3 (3) derivative, juglone (5hydroxy-1,4-naphthoquinone, 4 of Fig. 1), conjugated with fatty acids such as 5-O-acyl juglones (5a–j of Fig. 1) were stronger pol inhibitors than juglone alone (4) [23], ten 5-O-acylated derivatives of plumbagin (2a–j of Fig. 1) were chemically synthesized from plumbagin (1) and fatty acids to compare with 5-O-acyl juglones (5a–j)
Summary
Cancer is a major global public health problem. Epidemiological and animal studies have indicated that chemopreventive natural products are associated with a reduced risk of cancer development [1,2]. Selective inhibitors of DNA polymerases (pols) are considered potentially useful anti-cancer, anti-viral, anti-parasitic, and anti-pregnancy agents because some are known to suppress human cancer and normal cell proliferation, and are cytotoxic [3,4]. The human genome encodes at least 15 DNA pols, which function in cellular DNA synthesis [6,7]. Eukaryotic cells contain three replicative pols (a, d, and e), one mitochondrial pol (c), and at least 11 nonreplicative pols [b, f, g, h, i, k, l, m, n, terminal deoxynucleotidyl transferase (TdT), and REV1] [8,9]. We have studied selective inhibitors of each pol derived from natural products including food materials and nutrients for more than 18 years [10,11]. We have found that vitamin K3, but not K1 or K2, is a potent inhibitor of human pol c [12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
