Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics
2019
Autori
Grahovac, JelenaSrdić-Rajić, Tatjana
Santibanez, Juan F.
Pavlović, Marijana
Cavić, Milena
Radulović, Siniša
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Objective: 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 PPAR gamma, on melanoma cells as a potential agent for repurposing in melanoma treatment. Methods: Expression of AGTR1 and PPAR gamma 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. Results: Both AGT...R1 and PPAR gamma mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, 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 in vitro, and even sensitized vemurafenib-resistant cells to the treatment. Conclusions: 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.
Ključne reči:
Melanoma / telmisartan / apoptosis / mitochondria / reactive oxygen species / targeted therapyIzvor:
Cancer Biology & Medicine, 2019, 16, 2, 247-+Izdavač:
- Chinese Anti-Cancer Assoc, Tianjin
Finansiranje / projekti:
- Farmakodinamska i farmakogenomska ispitivanja novijih lekova u lečenju solidnih tumora (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41026)
- Ispitivanje patogeneze hematoloških maligniteta (RS-MESTD-Basic Research (BR or ON)-175053)
DOI: 10.20892/j.issn.2095-3941.2018.0375
ISSN: 2095-3941
PubMed: 31516746
WoS: 000469957500005
Scopus: 2-s2.0-85066961898
Institucija/grupa
Institut za medicinska istraživanjaTY - JOUR AU - Grahovac, Jelena AU - Srdić-Rajić, Tatjana AU - Santibanez, Juan F. AU - Pavlović, Marijana AU - Cavić, Milena AU - Radulović, Siniša PY - 2019 UR - http://rimi.imi.bg.ac.rs/handle/123456789/975 AB - Objective: 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 PPAR gamma, on melanoma cells as a potential agent for repurposing in melanoma treatment. Methods: Expression of AGTR1 and PPAR gamma 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. Results: Both AGTR1 and PPAR gamma mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, 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 in vitro, and even sensitized vemurafenib-resistant cells to the treatment. Conclusions: 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. PB - Chinese Anti-Cancer Assoc, Tianjin T2 - Cancer Biology & Medicine T1 - Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics EP - + IS - 2 SP - 247 VL - 16 DO - 10.20892/j.issn.2095-3941.2018.0375 ER -
@article{ author = "Grahovac, Jelena and Srdić-Rajić, Tatjana and Santibanez, Juan F. and Pavlović, Marijana and Cavić, Milena and Radulović, Siniša", year = "2019", abstract = "Objective: 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 PPAR gamma, on melanoma cells as a potential agent for repurposing in melanoma treatment. Methods: Expression of AGTR1 and PPAR gamma 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. Results: Both AGTR1 and PPAR gamma mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, 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 in vitro, and even sensitized vemurafenib-resistant cells to the treatment. Conclusions: 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.", publisher = "Chinese Anti-Cancer Assoc, Tianjin", journal = "Cancer Biology & Medicine", title = "Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics", pages = "+-247", number = "2", volume = "16", doi = "10.20892/j.issn.2095-3941.2018.0375" }
Grahovac, J., Srdić-Rajić, T., Santibanez, J. F., Pavlović, M., Cavić, M.,& Radulović, S.. (2019). Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. in Cancer Biology & Medicine Chinese Anti-Cancer Assoc, Tianjin., 16(2), 247-+. https://doi.org/10.20892/j.issn.2095-3941.2018.0375
Grahovac J, Srdić-Rajić T, Santibanez JF, Pavlović M, Cavić M, Radulović S. Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. in Cancer Biology & Medicine. 2019;16(2):247-+. doi:10.20892/j.issn.2095-3941.2018.0375 .
Grahovac, Jelena, Srdić-Rajić, Tatjana, Santibanez, Juan F., Pavlović, Marijana, Cavić, Milena, Radulović, Siniša, "Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics" in Cancer Biology & Medicine, 16, no. 2 (2019):247-+, https://doi.org/10.20892/j.issn.2095-3941.2018.0375 . .