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

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.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Ingels A,Dinhof C,Garg AD,Maddau L,Masi M,Evidente A,Berger W,Dejaegher B,Mathieu V

doi

10.1007/s00280-017-3293-x

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

971-983

issue

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-017-3293-x

journal_volume

pub_type

杂志文章

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