Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics
<b>Objective</b> Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are...
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2019-06-01
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| Series: | Cancer Biology & Medicine |
| Subjects: | |
| Online Access: | http://www.cancerbiomed.org/index.php/cocr/article/view/1420 |
| _version_ | 1818018263291920384 |
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| author | Jelena Grahovac Tatjana Srdi?-Raji? Juan Francisco Santiba?ez Marijana Pavlovi? Milena ?avi? Sini?a Radulovi? |
| author_facet | Jelena Grahovac Tatjana Srdi?-Raji? Juan Francisco Santiba?ez Marijana Pavlovi? Milena ?avi? Sini?a Radulovi? |
| author_sort | Jelena Grahovac |
| collection | DOAJ |
| description | <b>Objective</b> Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPARγ, on melanoma cells as a potential agent for repurposing in melanoma treatment.<b>Methods</b> Expression of AGTR1 and PPARγ mRNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index method.<b>Results</b> Both AGTR1 and PPARγ mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. <i>In vitro</i>, we found that telmisartan decreased melanoma cell viability by inducing cell apoptosis. Increased glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib <i>in vitro</i>, and even sensitized vemurafenib-resistant cells to the treatment.<b>Conclusions</b> Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression. |
| first_indexed | 2024-04-14T07:37:34Z |
| format | Article |
| id | doaj.art-601a8376a04548c2989c8ed195cf64ff |
| institution | Directory Open Access Journal |
| issn | 2095-3941 2095-3941 |
| language | English |
| last_indexed | 2024-04-14T07:37:34Z |
| publishDate | 2019-06-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj.art-601a8376a04548c2989c8ed195cf64ff2022-12-22T02:05:38ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412095-39412019-06-0116224726310.20892/j.issn.2095-3941.2018.03752018000375Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergeticsJelena Grahovac0Tatjana Srdi?-Raji?1Juan Francisco Santiba?ez2Marijana Pavlovi?3Milena ?avi?4Sini?a Radulovi?5Laboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade 11000, SerbiaLaboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade 11000, SerbiaDepartment of Molecular Oncology, Institute for Medical Research, University of Belgrade, Belgrade 11000, SerbiaLaboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade 11000, SerbiaLaboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade 11000, SerbiaLaboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade 11000, Serbia<b>Objective</b> Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPARγ, on melanoma cells as a potential agent for repurposing in melanoma treatment.<b>Methods</b> Expression of AGTR1 and PPARγ mRNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index method.<b>Results</b> Both AGTR1 and PPARγ mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. <i>In vitro</i>, we found that telmisartan decreased melanoma cell viability by inducing cell apoptosis. Increased glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib <i>in vitro</i>, and even sensitized vemurafenib-resistant cells to the treatment.<b>Conclusions</b> Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.http://www.cancerbiomed.org/index.php/cocr/article/view/1420Melanomatelmisartanapoptosismitochondriareactive oxygen speciestargeted therapy |
| spellingShingle | Jelena Grahovac Tatjana Srdi?-Raji? Juan Francisco Santiba?ez Marijana Pavlovi? Milena ?avi? Sini?a Radulovi? Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics Cancer Biology & Medicine Melanoma telmisartan apoptosis mitochondria reactive oxygen species targeted therapy |
| title | Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics |
| title_full | Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics |
| title_fullStr | Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics |
| title_full_unstemmed | Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics |
| title_short | Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib <i>in vitro</i> by altering cell bioenergetics |
| title_sort | telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib i in vitro i by altering cell bioenergetics |
| topic | Melanoma telmisartan apoptosis mitochondria reactive oxygen species targeted therapy |
| url | http://www.cancerbiomed.org/index.php/cocr/article/view/1420 |
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