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Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 5, pp 971–983 | Cite as

Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas

  • Aude Ingels
  • Carina Dinhof
  • Abhishek D. Garg
  • Lucia Maddau
  • Marco Masi
  • Antonio Evidente
  • Walter Berger
  • Bieke Dejaegher
  • Véronique MathieuEmail author
Original Article

Abstract

Purpose

Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apoptosis via cell volume dysregulation. This work studied its in vitro combination with cytotoxic chemotherapeutics in a rational manner.

Methods

Four melanoma cell lines harboring different sensitivity levels to pro-apoptotic stimuli were used to build a predictive response surface model allowing the determination of the optimal in vitro combinations of Sph A with two drugs, i.e., cisplatin or temozolomide, owing to a limited set of experimentations.

Results

Testing 12 experimental combinations allowed us to build an accurate predictive model that considers the complexity of the drug interaction and determines the optimal combinations according to the endpoint chosen, i.e., the maximal cytotoxic effects. Therefore, combining 4 µM Sph A with 75 µM cisplatin concomitantly for 72 h improved its cytotoxic effects on melanoma cells in a synergistic manner. An optimal in vitro treatment schedule was also obtained for temozolomide.

Conclusions

The use of a response surface model offers the possibility of reducing the experiments while determining accurately the optimal combinations. We herein highlighted that combining the Na+/K+/2Cl cotransporter and/or anion exchanger inhibitor Sph A with chemotherapeutic agents could improve the therapeutic benefits of conventional chemotherapies against advanced melanomas, particularly because Sph A exerts cytotoxic effects regardless of the genetic BRAF and NRAS status.

Keywords

Melanoma Apoptosis Combination therapy Sphaeropsidin A Cisplatin Temozolomide 

Abbreviations

ADME

Absorption, distribution, metabolism, and excretion

AUC

Area under the curve

CDDP

Cisplatin

Cmax

Maximum (or peak) serum concentration

CTLA-4

Cytotoxic T lymphocyte antigen-4

DTIC

Dacarbazine

EDTA

Ethylenediaminetetraacetic acid

GI50

Growth inhibition 50%

GST

Glutathione-S-transferase

LC50/90

Lethal concentration 50/90

MCDM

Multi-criteria decision-making

MDR

Multidrug resistance

MTIC

5-(3-methyltriazen-1-yl)imidazole-4-carboxamide

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCI

National cancer institute

NKCC1/2

Na+–K+–2Cl co-transporters ½

PBS

Phosphate buffered saline

PD1

Programmed cell death protein 1

PFS

Progression-free survival

RVI

Regulatory volume increase

Sph A

Sphaeropsidin A

TMZ

Temozolomide

Notes

Acknowledgements

We thank Robert Kiss for his advice in the current project and particularly for having initiated it as well as for reviewing the present manuscript. ADG is a postdoctoral fellow of the FWO-Vlaanderen, Belgium.

Funding

No private or public grant supported this work that was conducted with academic financial support only.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

280_2017_3293_MOESM1_ESM.docx (84 kb)
Supplementary material 1 (DOCX 84 KB)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Aude Ingels
    • 1
  • Carina Dinhof
    • 2
    • 3
  • Abhishek D. Garg
    • 4
  • Lucia Maddau
    • 5
  • Marco Masi
    • 6
  • Antonio Evidente
    • 6
  • Walter Berger
    • 2
    • 3
  • Bieke Dejaegher
    • 7
  • Véronique Mathieu
    • 1
    Email author
  1. 1.Laboratoire de Cancérologie et Toxicologie ExpérimentaleUniversité Libre de BruxellesIxellesBelgium
  2. 2.Department of Medicine I, Institute of Cancer ResearchMedical University ViennaViennaAustria
  3. 3.Comprehensive Cancer CenterMedical University ViennaViennaAustria
  4. 4.Laboratory for Cell Death Research and Therapy (CDRT), Department of Cellular and Molecular MedicineKU Leuven UniversityLeuvenBelgium
  5. 5.Dipartimento di Agraria, Sezione di Patologia vegetale ed EntomologiaUniversità degli Studi di SassariSassariItaly
  6. 6.Dipartimento di Scienze ChimicheUniversita’ di Napoli Federico IINapoliItaly
  7. 7.Laboratoire d’Analyse Instrumentale et de BioélectrochimieUniversité Libre de BruxellesIxellesBelgium

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