| Author | Garcia, Diogo Gomes | |
| Author | Faria Neto, Hugo Caire de Castro | |
| Author | Silva, Camila Ignácio da | |
| Author | Souza, Kauê Francisco Correa de Souza e | |
| Author | Albuquerque, Cassiano Felippe Gonçalves de | |
| Author | Silva, Adriana Ribeiro | |
| Author | Amorim, Lidia Maria da Fonte de | |
| Author | Freire, Aline Soares | |
| Author | Santelli, Ricardo Erthal | |
| Author | Diniz, Luan Pereira | |
| Author | Gomes, Flávia Carvalho Alcantara | |
| Author | Faria, Mauro Velho de Castro | |
| Author | Burth, Patrícia | |
| Access date | 2015-08-19T13:49:21Z | |
| Available date | 2015-08-19T13:49:21Z | |
| Document date | 2015 | |
| Citation | GARCIA, Diogo Gomes; et al. Na/K-ATPase as a target for anticancer drugs: studies with perillyl alcohol. Molecular Cancer , v.14, n.105, 14p, 2015. | pt_BR |
| ISSN | 1476-4598 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/11493 | |
| Language | eng | pt_BR |
| Publisher | BioMed Central | pt_BR |
| Rights | open access | |
| Title | Na/K-ATPase as a target for anticancer drugs: studies with perillyl alcohol | pt_BR |
| Type | Article | |
| DOI | 10.1186/s12943-015-0374-5 | pt_BR |
| Abstract | Background: Na/K-ATPase (NKA) is inhibited by perillyl alcohol (POH), a monoterpene used in the treatment of
tumors, including brain tumors. The NKA α1 subunit is known to be superexpressed in glioblastoma cells (GBM).
This isoform is embedded in caveolar structures and is probably responsible for the signaling properties of NKA
during apoptosis. In this work, we showed that POH acts in signaling cascades associated with NKA that control cell
proliferation and/or cellular death.
Methods: NKA activity was measured by the amount of non-radioactive Rb+ incorporation into cultured GBM cell
lines (U87 and U251) and non-tumor cells (mouse astrocytes and VERO cells). Cell viability was measured by lactate
dehydrogenase levels in the supernatants of POH-treated cells. Activated c-Jun N-terminal Kinase (JNK) and p38
were assessed by western blotting. Apoptosis was detected by flow cytometry and immunocytochemistry, and the
release of interleukins was measured by ELISA.
Results: All four cell types tested showed a similar sensitivity for POH. Perillic acid (PA), the main metabolite of
POH, did not show any effect on these cells. Though the cell viability decreased in a dose-dependent manner when
cells were treated with POH, the maximum cytotoxic effect of PA obtained was 30% at 4 mM. 1.5 mM POH activated
p38 in U87 cells and JNK in both U87 and U251 cells as well as mouse astrocytes. Dasatinib (an inhibitor of the
Src kinase family) and methyl β-cyclodextrin (which promotes cholesterol depletion in cell membranes) reduced
the POH-induced activation of JNK1/2 in U87 cells, indicating that the NKA-Src complex participates in this mechanism.
Inhibition of JNK1/2 by the JNK inhibitor V reduced the apoptosis of GBM cells that resulted from POH administration,
indicating the involvement of JNK1/2 in programmed cell death. 1.5 mM POH increased the production of interleukin
IL-8 in the U251 cell supernatant, which may indicate a possible strategy by which cells avoid the cytotoxic effects of POH.
Conclusions: A signaling mechanism mediated by NKA may have an important role in the anti-tumor action of POH in
GBM cells. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Analítica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Analítica. Rio de Janeiro, RJ, Brasil | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade do Estado do Rio de Janeiro. Faculdade de Ciências Médicas. Departamento de Medicina Interna. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil. | pt_BR |
| Subject | Na/K-ATPase | pt_BR |
| Subject | Perillyl alcohol | pt_BR |
| Subject | JNK | pt_BR |
| Subject | U87 and U251 glioma cells | pt_BR |
| DeCS | Proteínas Quinases JNK Ativadas por Mitógeno | pt_BR |
| DeCS | Neoplasias Encefálicas | pt_BR |
