title: Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase.
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.
authors: 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. vemathie@ulb.ac.be.
authors: Véronique
authors: V
authors: Mathieu
authors: Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest", Tours, France.
authors: Aurélie
authors: A
authors: Chantôme
authors: Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors: Florence
authors: F
authors: Lefranc
authors: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy.
authors: Alessio
authors: A
authors: Cimmino
authors: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Miklos
authors: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors: Verena
authors: V
authors: Paulitschke
authors: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Mohr
authors: Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100, Sassari, Italy.
authors: Lucia
authors: L
authors: Maddau
authors: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors: Alexander
authors: A
authors: Kornienko
authors: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Berger
authors: Inserm UMR 1069, Université François Rabelais and network "Ion channels and cancer - Canceropole Grand Ouest", Tours, France.
authors: Christophe
authors: C
authors: Vandier
authors: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Naples, Italy.
authors: Antonio
authors: A
authors: Evidente
authors: Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN, USA.
authors: Eric
authors: E
authors: Delpire
authors: 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.
authors: Robert
authors: R
authors: Kiss
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000187:drug effects*; D051379:Mice; D018715:Microscopy, Video; D015394:Molecular Structure; D011419:Propidium; D014343:Trypan Blue
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D011419:Propidium; C570422:sphaeropsidin A; D014343:Trypan Blue
keywords: Anion exchanger; Apoptosis; Cell volume; Cl−/HCO3 −; Ion transporter; Melanoma; NKCC1; Sphaeropsidin A