caa a22 4500 606174958 CHVBK 20210128100740.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00018-015-1902-6 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1902-6 Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase [Elektronische Daten] [Véronique Mathieu, Aurélie Chantôme, Florence Lefranc, Alessio Cimmino, Walter Miklos, Verena Paulitschke, Thomas Mohr, Lucia Maddau, Alexander Kornienko, Walter Berger, Christophe Vandier, Antonio Evidente, Eric Delpire, Robert Kiss] 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. 10µM 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− andthe 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. Springer Basel, 2015 Melanoma nationallicence Sphaeropsidin A nationallicence Apoptosis nationallicence Ion transporter nationallicence Cell volume nationallicence NKCC1 nationallicence Anion exchanger nationallicence Cl−/HCO3 − nationallicence Mathieu Véronique Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Campus de la Plaine, Boulevard du Triomphe, 1050, Brussels, Belgium aut Chantôme Aurélie Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest”, Tours, France aut Lefranc Florence Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium aut Cimmino Alessio Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy aut Miklos Walter Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut Paulitschke Verena Department of Dermatology, Medical University of Vienna, Vienna, Austria aut Mohr Thomas Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut Maddau Lucia Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100, Sassari, Italy aut Kornienko Alexander Department of Chemistry and Biochemistry, Texas State University, 78666, San Marcos, TX, USA aut Berger Walter Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut Vandier Christophe Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest”, Tours, France aut Evidente Antonio Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy aut Delpire Eric Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN, USA aut Kiss Robert Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Campus de la Plaine, Boulevard du Triomphe, 1050, Brussels, Belgium aut Cellular and Molecular Life Sciences Springer Basel 72/19(2015-10-01), 3731-3746 1420-682X 72:19<3731 2015 72 18 https://doi.org/10.1007/s00018-015-1902-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1902-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mathieu Véronique Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Campus de la Plaine, Boulevard du Triomphe, 1050, Brussels, Belgium aut NATIONALLICENCE 700 1- Chantôme Aurélie Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest”, Tours, France aut NATIONALLICENCE 700 1- Lefranc Florence Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium aut NATIONALLICENCE 700 1- Cimmino Alessio Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy aut NATIONALLICENCE 700 1- Miklos Walter Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut NATIONALLICENCE 700 1- Paulitschke Verena Department of Dermatology, Medical University of Vienna, Vienna, Austria aut NATIONALLICENCE 700 1- Mohr Thomas Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut NATIONALLICENCE 700 1- Maddau Lucia Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100, Sassari, Italy aut NATIONALLICENCE 700 1- Kornienko Alexander Department of Chemistry and Biochemistry, Texas State University, 78666, San Marcos, TX, USA aut NATIONALLICENCE 700 1- Berger Walter Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria aut NATIONALLICENCE 700 1- Vandier Christophe Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest”, Tours, France aut NATIONALLICENCE 700 1- Evidente Antonio Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy aut NATIONALLICENCE 700 1- Delpire Eric Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN, USA aut NATIONALLICENCE 700 1- Kiss Robert Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Campus de la Plaine, Boulevard du Triomphe, 1050, Brussels, Belgium aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/19(2015-10-01), 3731-3746 1420-682X 72:19<3731 2015 72 18