Drug Repurposing Approach Identifies a Synergistic Drug Combination of an Antifungal Agent and an Experimental Organometallic Drug for Melanoma Treatment.
- Riedel T Laboratory of Organometallic and Medicinal Chemistry, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL) , 1015 Lausanne, Switzerland.
- Demaria O Department of Dermatology, University Hospital of Lausanne , 1011 Lausanne, Switzerland.
- Zava O Laboratory of Organometallic and Medicinal Chemistry, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL) , 1015 Lausanne, Switzerland.
- Joncic A Department of Dermatology, University Hospital of Lausanne , 1011 Lausanne, Switzerland.
- Gilliet M Department of Dermatology, University Hospital of Lausanne , 1011 Lausanne, Switzerland.
- Dyson PJ Laboratory of Organometallic and Medicinal Chemistry, Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL) , 1015 Lausanne, Switzerland.
- 2017-11-30
Published in:
- Molecular pharmaceutics. - 2018
RAPTA-T
antifungal agent
drug discovery
haloprogin
high-throughput screening
melanoma
organometallic drug
Animals
Antifungal Agents
Antineoplastic Agents
Cell Survival
Drug Repositioning
Drug Synergism
Female
Flow Cytometry
Melanoma
Mice
Mice, Inbred C57BL
Organometallic Compounds
Phenyl Ethers
Skin Neoplasms
English
By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1021/acs.molpharmaceut.7b00764
- PMID 29185769
- Persistent URL
- https://sonar.ch/global/documents/46254
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