Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas
- 198 Downloads
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.
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.
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.
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.
KeywordsMelanoma Apoptosis Combination therapy Sphaeropsidin A Cisplatin Temozolomide
Absorption, distribution, metabolism, and excretion
Area under the curve
Maximum (or peak) serum concentration
Cytotoxic T lymphocyte antigen-4
Growth inhibition 50%
Lethal concentration 50/90
National cancer institute
Na+–K+–2Cl− co-transporters ½
Phosphate buffered saline
Programmed cell death protein 1
Regulatory volume increase
- Sph A
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.
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.