The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells
Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Cell Physiol Biochem Press GmbH & Co KG
2017-08-01
|
| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | http://www.karger.com/Article/FullText/480328 |
| _version_ | 1817991332268867584 |
|---|---|
| author | Giada Catalogna Cristina Talarico Vincenzo Dattilo Vincenzo Gangemi Ferdinando Calabria Lucia D’Antona Silvia Schenone Francesca Musumeci Cataldo Bianco Nicola Perrotti Rosario Amato Giuseppe L. Cascini |
| author_facet | Giada Catalogna Cristina Talarico Vincenzo Dattilo Vincenzo Gangemi Ferdinando Calabria Lucia D’Antona Silvia Schenone Francesca Musumeci Cataldo Bianco Nicola Perrotti Rosario Amato Giuseppe L. Cascini |
| author_sort | Giada Catalogna |
| collection | DOAJ |
| description | Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. Results: We demonstrate here, that i) 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells. |
| first_indexed | 2024-04-14T01:11:57Z |
| format | Article |
| id | doaj.art-3cf5dbdeede746439b80a95cba269c45 |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-04-14T01:11:57Z |
| publishDate | 2017-08-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-3cf5dbdeede746439b80a95cba269c452022-12-22T02:21:01ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782017-08-0143110811910.1159/000480328480328The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme CellsGiada CatalognaCristina TalaricoVincenzo DattiloVincenzo GangemiFerdinando CalabriaLucia D’AntonaSilvia SchenoneFrancesca MusumeciCataldo BiancoNicola PerrottiRosario AmatoGiuseppe L. CasciniBackground/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. Results: We demonstrate here, that i) 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells.http://www.karger.com/Article/FullText/480328SGK1GBM64CuCl2SI113 |
| spellingShingle | Giada Catalogna Cristina Talarico Vincenzo Dattilo Vincenzo Gangemi Ferdinando Calabria Lucia D’Antona Silvia Schenone Francesca Musumeci Cataldo Bianco Nicola Perrotti Rosario Amato Giuseppe L. Cascini The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells Cellular Physiology and Biochemistry SGK1 GBM 64CuCl2 SI113 |
| title | The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells |
| title_full | The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells |
| title_fullStr | The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells |
| title_full_unstemmed | The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells |
| title_short | The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells |
| title_sort | sgk1 kinase inhibitor si113 sensitizes theranostic effects of the 64cucl2 in human glioblastoma multiforme cells |
| topic | SGK1 GBM 64CuCl2 SI113 |
| url | http://www.karger.com/Article/FullText/480328 |
| work_keys_str_mv | AT giadacatalogna thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT cristinatalarico thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT vincenzodattilo thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT vincenzogangemi thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT ferdinandocalabria thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT luciadantona thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT silviaschenone thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT francescamusumeci thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT cataldobianco thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT nicolaperrotti thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT rosarioamato thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT giuseppelcascini thesgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT giadacatalogna sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT cristinatalarico sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT vincenzodattilo sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT vincenzogangemi sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT ferdinandocalabria sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT luciadantona sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT silviaschenone sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT francescamusumeci sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT cataldobianco sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT nicolaperrotti sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT rosarioamato sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells AT giuseppelcascini sgk1kinaseinhibitorsi113sensitizestheranosticeffectsofthe64cucl2inhumanglioblastomamultiformecells |