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    Cellular and molecular life sciences : CMLS. 2015 Apr 14. doi: 10.1007/s00018-015-1902-6. pii: 10.1007/s00018-015-1902-6
    Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase.
    Mathieu V1,  Chantôme A2,  Lefranc F3,  Cimmino A4,  Miklos W5,  Paulitschke V6,  Mohr T7,  Maddau L8,  Kornienko A9,  Berger W10,  Vandier C11,  Evidente A12,  Delpire E13,  Kiss R14
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    Abstract

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 µM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl(-) and the decreased HCO3 (-) concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na-K-2Cl electroneutral cotransporter or Cl(-)/HCO3 (-) anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells.


    KEYWORDS: Anion exchanger, Apoptosis, Cell volume, Cl−/HCO3 −, Ion transporter, Melanoma, NKCC1, Sphaeropsidin A

    Publikations ID: 25868554
    Quelle: öffnen
     
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