Hypericin affects cancer side populations via competitive inhibition of BCRP
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
29665654
DOI
10.1016/j.biopha.2018.01.074
PII: S0753-3322(17)36101-2
Knihovny.cz E-zdroje
- Klíčová slova
- ABC transporters, Cancer stem-like cells, Drug resistance, Hypericin, Side population, St. John’s wort,
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- aldehyddehydrogenasa metabolismus MeSH
- analýza přežití MeSH
- anthraceny MeSH
- buněčné klony MeSH
- buněčné sféroidy účinky léků metabolismus patologie MeSH
- fenotyp MeSH
- karcinogeneze účinky léků metabolismus patologie MeSH
- lidé MeSH
- myši SCID MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky účinky léků metabolismus patologie MeSH
- nádorové proteiny metabolismus MeSH
- nádory metabolismus patologie MeSH
- P-glykoprotein metabolismus MeSH
- perylen analogy a deriváty farmakologie MeSH
- substrátová specifita účinky léků MeSH
- vedlejší populace buněk účinky léků patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABC transportér z rodiny G, člen 2 MeSH
- ABCG2 protein, human MeSH Prohlížeč
- aldehyddehydrogenasa MeSH
- anthraceny MeSH
- hypericin MeSH Prohlížeč
- nádorové biomarkery MeSH
- nádorové proteiny MeSH
- P-glykoprotein MeSH
- perylen MeSH
OBJECTIVE: Cancer stem-like cells (CSLCs) are considered a root of tumorigenicity and resistance. However, their identification remains challenging. The use of the side population (SP) assay as a credible marker of CSLCs remains controversial. The SP assay relies on the elevated activity of ABC transporters that, in turn, can be modulated by hypericin (HYP), a photosensitizer and bioactive compound of St. John's Wort (Hypericum perforatum), a popular over-the-counter antidepressant. Here we aimed to comprehensively characterize the SP phenotype of cancer cells and to determine the impact of HYP on these cells. METHODS: Flow cytometry and sorting-based assays were employed, including CD24-, CD44-, CD133-, and ALDH-positivity, clonogenicity, 3D-forming ability, ABC transporter expression and activity, and intracellular accumulation of HYP/Hoechst 33342. The tumorigenic ability of SP, nonSP, and HYP-treated cells was verified by xenotransplantation into immunodeficient mice. RESULTS: The SP phenotype was associated with elevated expression of several investigated transporters and more intensive growth in non-adherent conditions but not with higher clonogenicity, tumorigenicity or ALDH-positivity. Despite stimulated BCRP level and MRP1 activity, HYP reversibly decreased the SP proportion, presumably via competitive inhibition of BCRP. HYP-selected SP cells acquired additional traits of resistance and extensively eliminated HYP. CONCLUSIONS: Our results suggest that SP is not an unequivocal CSLC-marker. However, SP could play an important role in modulating HYP-treatment and serve as a negative predictive tool for HYP-based therapies. Moreover, the use of supplements containing HYP by cancer patients should be carefully considered, due to its proposed effect on drug efflux and complex impact on tumor cells, which have not yet been sufficiently characterized.
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