| Added by | pmartino |
|---|---|
| Group name | EquipePM |
| Item Type | Journal Article |
| Title | Imidazoquinoxaline anticancer derivatives and imiquimod interact with tubulin: Characterization of molecular microtubule inhibiting mechanisms in correlation with cytotoxicity |
| Creator | Courbet et al. |
| Author | Alexis Courbet |
| Author | Nicole Bec |
| Author | Caroline Constant |
| Author | Christian Larroque |
| Author | Safia El Messaoudi |
| Author | Zahraa Zghaib |
| Author | Sonia Khier |
| Author | Carine Deleuze-Masquefa |
| Author | Florence Gattacceca |
| Abstract | Displaying a strong antiproliferative activity on a wide variety of cancer cells, EAPB0203 and EAPB0503 belong to the imidazo[1,2-a]quinoxalines family of imiquimod structural analogues. EAPB0503 has been shown to inhibit tubulin polymerization. The aim of the present study is to characterize the interaction of EAPB0203 and EAPB0503 with tubulin. We combine experimental approaches at the cellular and the molecular level both in vitro and in silico in order to evaluate the interaction of EAPB0203 and EAPB0503 with tubulin. We examine the influence of EAPB0203 and EAPB0503 on the cell cycle and fate, explore the binding interaction with purified tubulin, and use a computational molecular docking model to determine the binding modes to the microtubule. We then use a drug combination study with other anti-microtubule agents to compare the binding site of EAPB0203 and EAPB0503 to known potent tubulin inhibitors. We demonstrate that EAPB0203 and EAPB0503 are capable of blocking human melanoma cells in G2 and M phases and inducing cell death and apoptosis. Second, we show that EAPB0203 and EAPB0503, but also unexpectedly imiquimod, bind directly to purified tubulin and inhibit tubulin polymerization. As suggested by molecular docking and binding competition studies, we identify the colchicine binding site on ?-tubulin as the interaction pocket. Furthermore, we find that EAPB0203, EAPB0503 and imiquimod display antagonistic cytotoxic effect when combined with colchicine, and disrupt tubulin network in human melanoma cells. We conclude that EAPB0203, EAPB0503, as well as imiquimod, interact with tubulin through the colchicine binding site, and that the cytotoxic activity of EAPB0203, EAPB0503 and imiquimod is correlated to their tubulin inhibiting effect. These compounds appear as interesting anticancer drug candidates as suggested by their activity and mechanism of action, and deserve further investigation for their use in the clinic. |
| Publication | PloS One |
| Volume | 12 |
| Issue | 8 |
| Pages | e0182022 |
| Date | 2017 |
| Journal Abbr | PLoS ONE |
| Language | eng |
| DOI | 10.1371/journal.pone.0182022 |
| ISSN | 1932-6203 |
| Short Title | Imidazoquinoxaline anticancer derivatives and imiquimod interact with tubulin |
| Library Catalog | PubMed |
| Call Number | IMPACT: 2.766 |
| Extra | IMPACT: 2.766 PMID: 28797090 PMCID: PMC5552358 |
| Tags | Antineoplastic Agents, Apoptosis, Binding Sites, Cell Cycle, Cell Death, Cell Line, Tumor, Cell Proliferation, Colchicine, Computer Simulation, Humans, Models, Molecular, Molecular Docking Simulation, original, pp2i, Protein Binding, Quinoxalines, Tubulin, Tubulin Modulators |
| Date Added | 2018/07/20 - 09:39:46 |
| Date Modified | 2021/03/05 - 10:46:36 |
Institut de Recherche en Cancérologie de
