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Published on: January 11, 2019
Transcriptomic classification of antitumor agents: application to the analysis of the antitumoral effect of SR31747A
Jean-Bernard Ferrini1, Omar Jbilo, Annick Peleraux
1Immunology-Oncology Department, Sanofi-Synthelabo Recherche, 371 rue Prof. Blayac, F-34184 Montpellier 04, France.
Abstract:
SR31747A is a sigma ligand that exhibits a potent antitumoral activity on various human tumor cell lines both in vitro and in vivo. To understand its mode of action, we used DNA microarray technology combined with a new bioinformatic approach to identify genes that are modulated by SR31747A in different human breast or prostate cancer cell lines. The SR31747A transcriptional signature was also compared with that of seven different representative anticancer drugs commonly used in the clinic. To this aim, we performed a two-dimensional hierarchical clustering analysis of drugs and genes which showed that 1) standard molecules with similar mechanism of action clustered together and 2) SR31747A does not belong to any previously characterized class of standard anticancer drugs. Moreover, we showed that 3) SR31747A mainly exerted its antiproliferative effect by inhibiting the expression of genes playing a key role in DNA replication and cell cycle progression. Finally, contrasting with other drugs, we obtained evidence that 4) SR31747A strongly inhibited the expression of three key enzymes of the nucleotide synthesis pathway (i.e., dihydrofolate reductase, thymidylate synthase, and thymidine kinase) with the latter shown both at the mRNA and protein levels. These results, obtained through a novel molecular approach to characterize and compare anticancer agents, showed that SR31747A exhibits an original mechanism of action, very likely through unexpected targets whose modulations may account for its antitumoral effect.
Insights
SR31747A, a sigma ligand, shows potent anti-tumor effects by uniquely inhibiting DNA replication and nucleotide synthesis genes. This novel anticancer agent does not fit existing drug classifications, suggesting new therapeutic targets.
Area of Science:
- Pharmacology
- Molecular Biology
- Bioinformatics
Background:
- SR31747A is a sigma ligand with demonstrated in vitro and in vivo antitumoral activity against various human cancer cell lines.
- Understanding the precise mechanism of action for novel anticancer agents is crucial for drug development and clinical application.
Purpose of the Study:
- To elucidate the molecular mechanism of action of SR31747A using gene expression profiling.
- To compare the transcriptional signature of SR31747A with established anticancer drugs to determine its classification and identify potential novel targets.
Main Methods:
- DNA microarray technology was employed to identify genes modulated by SR31747A in human breast and prostate cancer cell lines.
- A bioinformatic approach, including two-dimensional hierarchical clustering, was used to analyze gene expression data and compare SR31747A with other anticancer drugs.
Main Results:
- SR31747A's transcriptional signature did not cluster with any known class of anticancer drugs, indicating a novel mechanism of action.
- SR31747A primarily inhibits gene expression involved in DNA replication and cell cycle progression.
- The drug significantly suppressed key enzymes in nucleotide synthesis, including dihydrofolate reductase, thymidylate synthase, and thymidine kinase, at both mRNA and protein levels.
Conclusions:
- SR31747A exhibits an original anticancer mechanism of action, distinct from currently characterized drugs.
- The inhibition of nucleotide synthesis pathway enzymes and DNA replication genes likely contributes to SR31747A's antitumoral effects.
- This study highlights a novel molecular approach for characterizing and comparing anticancer agents, revealing SR31747A's potential through unexpected targets.
