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Bismuth flavonol complexes: investigating membrane permeability and in vitro activity in human colorectal cancer
Serafina M C Crapis1,2, Stephen A Holt3, Philip C Andrews4
1School of Science, University of Wollongong, Wollongong, NSW, 2522, Australia. carolynd@uow.edu.au.
Abstract:
In this study the biological activity of novel bismuth-flavonol (BiFlav) complexes has been explored in colorectal cancer cells to determine their potential as anti-cancer therapeutic agents. The work derives from the fact that dietary flavonols exhibit well established anti-oxidant and anti-cancer properties while bismuth compounds are marketed for gastrointestinal therapy. The membrane permeability properties and in vitro anti-cancer activities of heteroleptic and homoleptic BiFlav complexes (BiPh(Flav)2, BiPh(BrFlav)2 and Bi(BrFlav)3; Ph = phenyl, Flav = 3-hydroxyflavone, BrFlav = 4-bromo-3-hydroxyflavone), are presented. Electrochemical impedance spectroscopy and neutron reflectometry studies revealed significant alterations in membrane structure, especially by BiPh(Flav)2. Cellular uptake studies (performed by graphite furnace atomic absorption spectroscopy) across human colorectal cancer (CRC) cell lines (HCT-8, HCT-116, and HT-29) showed cell-specific differences in bismuth accumulation, with BiPh(Flav)2 exhibiting the highest cellular uptake and retention. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assays showed significantly greater toxicity (lower IC50 values) of BiFlav complexes compared to the free flavonols. BiPh(Flav)2 demonstrated the highest cytotoxicity, particularly in HCT-116 cells (2.63 µM), followed by HT-29 (6.57 µM) and HCT-8 (8.92 µM). Brominated derivatives, such as BiPh(BrFlav)2 and Bi(BrFlav)3, which exhibited membrane retention, showed only moderate cytotoxicity (8.42 µM and 26.2 µM respectively, HCT-8 cells). MTT assays were also conducted with human peripheral blood mononuclear cells (PBMCs) where BiPh(BrFlav)2 demonstrated reduced cytotoxicity (23.3 µM) and favourable selectivity indices (>2) across CRC cell lines. These findings highlight the therapeutic potential of BiFlav complexes through multi-faceted mechanisms involving both membrane disruption and intracellular interactions, offering a foundation for their further investigation for targeted colorectal cancer therapy.
