ABSTRACT
Title
A novel mechanism of action of RDC11: the targeting of the HIF-1 and mTOR pathways.
Authors
V. Vidimar1,2, D. Guenot3, M. Pfeffer4, A. Bergamo1, G. Sava1, JP. Loeffler2 and C. Gaiddon2
1 Callerio Foundation Onlus, Trieste, Italy; Dept of Pharmacology and Toxicology, University of Padova, Italy
2 INSERM U692, Laboratoire de signalisations moléculaires et neurodégénérescence, University of Strasbourg, France
3 EA 4438, Physiopathologie et Médecine Translationnelle, University of Strasbourg, France
4 UMR 7177, Laboratoire de Synthèses Métallo-Induites, University of Strasbourg, France
Abstract
Cisplatin is one of the most used anticancer drugs, as it is administered to 50-70% of all patients suffering from cancer, usually in combination with other drugs. It targets rapidly dividing cells, including cancer cells but also healthy tissues, therefore displaying severe side effects due to its poor selectivity. Several lead organometallic molecules have been tested with the aim of overcoming this issue, including the ruthenium-derived compound RDC11, which showed interesting in vivo anticancer activities in multiple models [1]. The lack of a strong correlation between the interaction with DNA and its cytotoxic activity [1] has suggested alternative modes of action for this compound.
Affimetrix microarray analysis performed in our lab showed for the first time that RDC11 is able to influence the transcriptional activation of different genes of mTOR and HIF-1 alpha pathways, two of the most relevant pathways for cancer cell viability. mTOR is a protein kinase that controls cell growth by regulating protein synthesis and autophagy [2]. HIF-1 is a transcription factor stabilized in response to hypoxic stress and involved in cell survival and angiogenesis [3]. HIF-1 is usually inactive under physiological conditions but active in many solid tumors. The targeting of HIF-1 could then represent a mechanism of selective cytotoxicity towards cancer cells.
Our results indicate that RDC11, unlike cisplatin, decreased HIF-1 alpha protein levels in both SW480 and HCT116 colon adenocarcinoma cell lines maintained in hypoxia. We observed the same effect of RDC11 on HIF-1 alpha levels when hypoxia was induced chemically with deferoxamine mesylate in HCT116 cells.
Moreover, RT-qPCR showed that RDC11 treatment decreased the expression levels of different HIF-1 alpha target genes such as GLUT-1 and VEGF, and some mTOR target genes, such as RAPTOR and RICTOR, in HCT116 cells in both normoxia and DFO-induced hypoxia, as well as HIF-1 alpha and HIF-1 beta genes.
These results indicate that RDC11 may exert its antitumoral activity chiefly by impairing the activity of mTOR and HIF-1 pathways, and this would represent, so far, a unique mechanism of action for an organometallic anticancer compound. We are now trying to assess the relevance of this inhibition in cancer cell phisiology and to understand which is the underlying molecular mechanism. The identification of RDC11 pharmacological targets could indeed pave the way for selective optimization of the drug itself, potentially leading to a “targeted therapy”, which is the main challenge of cancer chemotherapy today.
1) Meng X et al (2009) - Cancer Res 69:5458.
2) Guertin DA, Sabatini DM (2005) - Trends Mol Med 2005 8:353.
3) Semenza GL (2003) - Nat Rev Cancer 3:721.
Affimetrix microarray analysis performed in our lab showed for the first time that RDC11 is able to influence the transcriptional activation of different genes of mTOR and HIF-1 alpha pathways, two of the most relevant pathways for cancer cell viability. mTOR is a protein kinase that controls cell growth by regulating protein synthesis and autophagy [2]. HIF-1 is a transcription factor stabilized in response to hypoxic stress and involved in cell survival and angiogenesis [3]. HIF-1 is usually inactive under physiological conditions but active in many solid tumors. The targeting of HIF-1 could then represent a mechanism of selective cytotoxicity towards cancer cells.
Our results indicate that RDC11, unlike cisplatin, decreased HIF-1 alpha protein levels in both SW480 and HCT116 colon adenocarcinoma cell lines maintained in hypoxia. We observed the same effect of RDC11 on HIF-1 alpha levels when hypoxia was induced chemically with deferoxamine mesylate in HCT116 cells.
Moreover, RT-qPCR showed that RDC11 treatment decreased the expression levels of different HIF-1 alpha target genes such as GLUT-1 and VEGF, and some mTOR target genes, such as RAPTOR and RICTOR, in HCT116 cells in both normoxia and DFO-induced hypoxia, as well as HIF-1 alpha and HIF-1 beta genes.
These results indicate that RDC11 may exert its antitumoral activity chiefly by impairing the activity of mTOR and HIF-1 pathways, and this would represent, so far, a unique mechanism of action for an organometallic anticancer compound. We are now trying to assess the relevance of this inhibition in cancer cell phisiology and to understand which is the underlying molecular mechanism. The identification of RDC11 pharmacological targets could indeed pave the way for selective optimization of the drug itself, potentially leading to a “targeted therapy”, which is the main challenge of cancer chemotherapy today.
1) Meng X et al (2009) - Cancer Res 69:5458.
2) Guertin DA, Sabatini DM (2005) - Trends Mol Med 2005 8:353.
3) Semenza GL (2003) - Nat Rev Cancer 3:721.