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Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

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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.

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Acknowledgments

R.K. is a director of research with the Fonds National de la Recherche Scientifique (FRS-FNRS; Belgium). E.D. is supported by NIH grants GM74771 and DK93501. A.K. acknowledges National Cancer Institute (Grant CA186046-01A1). A.C. and C.V. acknowledge University of Tours, INSERM, the "Région Centre" of France (LIPIDS project of ARD2020 Biomédicaments), the “Ligue Nationale Contre le Cancer”, Canceropole Grand Ouest, the Association “CANCEN” and Tours’ Hospital oncology association ACORT.”

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. 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

    Véronique Mathieu & Robert Kiss

  2. Inserm UMR 1069, Université François Rabelais and network “Ion channels and cancer - Canceropole Grand Ouest”, Tours, France

    Aurélie Chantôme & Christophe Vandier

  3. Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

    Florence Lefranc

  4. Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant’Angelo, Via Cintia 4, 80126, Naples, Italy

    Alessio Cimmino & Antonio Evidente

  5. Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Walter Miklos, Thomas Mohr & Walter Berger

  6. Department of Dermatology, Medical University of Vienna, Vienna, Austria

    Verena Paulitschke

  7. Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100, Sassari, Italy

    Lucia Maddau

  8. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA

    Alexander Kornienko

  9. Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN, USA

    Eric Delpire

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  1. Véronique Mathieu
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  2. Aurélie Chantôme
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  3. Florence Lefranc
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  4. Alessio Cimmino
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  5. Walter Miklos
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  13. Eric Delpire
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  14. Robert Kiss
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Correspondence to Véronique Mathieu.

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E. Delpire and R. Kiss are co-senior authors.

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Mathieu, V., Chantôme, A., Lefranc, F. et al. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase. Cell. Mol. Life Sci. 72, 3731–3746 (2015). https://doi.org/10.1007/s00018-015-1902-6

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