Abstract
By using a zebrafish embryo model to guide the chromatographic fractionation of antimitotic secondary metabolites, seven podophyllotoxin-type lignans were isolated from a hydroalcoholic extract obtained from the steam bark of Bursera fagaroides. The compounds were identified as podophyllotoxin (1), β-peltatin-A-methylether (2), 5′-desmethoxy-β-peltatin-A-methylether (3), desmethoxy-yatein (4), desoxypodophyllotoxin (5), burseranin (6), and acetyl podophyllotoxin (7). The biological effects on mitosis, cell migration, and microtubule cytoskeleton remodeling of lignans 1–7 were further evaluated in zebrafish embryos by whole-mount immunolocalization of the mitotic marker phospho-histone H3 and by a tubulin antibody. We found that lignans 1, 2, 4, and 7 induced mitotic arrest, delayed cell migration, and disrupted the microtubule cytoskeleton in zebrafish embryos. Furthermore, microtubule cytoskeleton destabilization was observed also in PC3 cells, except for 7. Therefore, these results demonstrate that the cytotoxic activity of 1, 2, and 4 is mediated by their microtubule-destabilizing activity. In general, the in vivo and in vitro models here used displayed equivalent mitotic effects, which allows us to conclude that the zebrafish model can be a fast and cheap in vivo model that can be used to identify antimitotic natural products through bioassay-guided fractionation.
Highlights
Lignans are a big family of secondary metabolites biosynthesized in plants through the shikimic acid pathway that represent an important class of compounds in cancer research studies [1,2].One of the most representative groups of lignans are the aryltetralin lignans [3]
24 h-old zebrafish embryos have been used to screen the effects of small chemical molecules on the cell cycle and the induction of mitotic arrest using whole-mount immunohistochemistry of H3S10ph [16]
We evaluated the effect of a B. fagaroides hydroalcoholic extract (HA) on mitotic arrest in whole 24 h post fertilization zebrafish embryos
Summary
One of the most representative groups of lignans are the aryltetralin lignans [3] Into this group of compounds, podophyllotoxin (1) is the most known because of its use as an effective antiviral for genital warts treatment. Molecules 2018, 23, x FOR PEER REVIEW of cancer cells [4] In vitro, it binds to the colchicine binding site [5,6]. Because of the unacceptable gastrointestinal toxicity, many semisynthetic podophyllotoxin derivatives were developed and tested of cancer cells [4]. Etoposide and teniposide are glycosylated derivatives podophyllotoxin gastrointestinal toxicity, many semisynthetic podophyllotoxin derivatives wereofdeveloped and developed in the
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