Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.
The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targ...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3465283?pdf=render |
| _version_ | 1818501676167856128 |
|---|---|
| author | Alessandro Furlan Benjamin Roux Fabienne Lamballe Filippo Conti Nathalie Issaly Fabrice Daian Jean-François Guillemot Sylvie Richelme Magali Contensin Joan Bosch Daniele Passarella Oreste Piccolo Rosanna Dono Flavio Maina |
| author_facet | Alessandro Furlan Benjamin Roux Fabienne Lamballe Filippo Conti Nathalie Issaly Fabrice Daian Jean-François Guillemot Sylvie Richelme Magali Contensin Joan Bosch Daniele Passarella Oreste Piccolo Rosanna Dono Flavio Maina |
| author_sort | Alessandro Furlan |
| collection | DOAJ |
| description | The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation. |
| first_indexed | 2024-12-10T20:59:32Z |
| format | Article |
| id | doaj.art-16f0abdacca84429aa5abd459002eb93 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T20:59:32Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-16f0abdacca84429aa5abd459002eb932022-12-22T01:33:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4673810.1371/journal.pone.0046738Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.Alessandro FurlanBenjamin RouxFabienne LamballeFilippo ContiNathalie IssalyFabrice DaianJean-François GuillemotSylvie RichelmeMagali ContensinJoan BoschDaniele PassarellaOreste PiccoloRosanna DonoFlavio MainaThe development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.http://europepmc.org/articles/PMC3465283?pdf=render |
| spellingShingle | Alessandro Furlan Benjamin Roux Fabienne Lamballe Filippo Conti Nathalie Issaly Fabrice Daian Jean-François Guillemot Sylvie Richelme Magali Contensin Joan Bosch Daniele Passarella Oreste Piccolo Rosanna Dono Flavio Maina Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. PLoS ONE |
| title | Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. |
| title_full | Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. |
| title_fullStr | Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. |
| title_full_unstemmed | Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. |
| title_short | Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. |
| title_sort | combined drug action of 2 phenylimidazo 2 1 b benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures |
| url | http://europepmc.org/articles/PMC3465283?pdf=render |
| work_keys_str_mv | AT alessandrofurlan combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT benjaminroux combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT fabiennelamballe combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT filippoconti combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT nathalieissaly combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT fabricedaian combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT jeanfrancoisguillemot combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT sylvierichelme combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT magalicontensin combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT joanbosch combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT danielepassarella combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT orestepiccolo combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT rosannadono combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures AT flaviomaina combineddrugactionof2phenylimidazo21bbenzothiazolederivativesoncancercellsaccordingtotheironcogenicmolecularsignatures |