VITAMIN K DERIVATIVES AS CANDIDATES OF WILD-TYPE p53 ACTIVATORS

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  • Presentation type: IC - Undergraduate Students
  • Track: Cellular Biology
  • Keywords: Vitamin K; p53; apoptosis;
  • 1 Universidade Federal do Rio de Janeiro
  • 2 Universidade Federal Fluminense
  • 3 Instituto de Química / Universidade Federal Fluminense

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Abstract

INTRODUCTION AND OBJECTIVES: p53 is a phosphoprotein composed of 53 kDa and 393 amino acids; it is encoded by the TP53 gene that is located on the short arm of chromosome 17. When active, p53 adopts a tetrameric form and is mostly regulated by the MDM2 protein. Known as a “guardian of the human genome”, p53, under stress conditions, is able to promote the cell cycle stop in the G1/S phase, the induction of p21, among other defense mechanisms, allowing the repair of DNA that was previously disabled. If these mechanisms fail, p53 protein triggers the apoptotic cascade signals and the cells can go to into apoptosis, preventing the error from spreading. There are few studies regarding the role of vitamin K in the activation of wild-type p53, however, there is evidence that vitamin K2 is capable of inducing apoptosis via p53 in hepatocarcinoma lines that express wild-type p53 (Smmc-7721). Bearing in mind that vitamin K2 induces apoptosis by activating wild-type p53, we aim to test a group of compounds designed from vitamin K, which can promote a similar effect, to clarify the mechanism of p53 activation in breast cancer cell lines that express wild type p53. MATERIALS AND METHODS: Vitamin K-derived compounds were screened by assessing cell viability using the MTT reduction technique in the MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53), breast cancer cell lines. In addition, the dose-response curve (IC50) of the selected compounds was performed after the cell viability test. RESULTS AND CONCLUSIONS: With screening assay, using the compounds at 10 µM, we observed that, after 72 h, six compounds were more effective to decreased the cellular viability of MCF-7 cells when compared to MDA-MB-231 cells. The compounds that decreased MCF-7 cell viability by 50% or more, when compared to the same treatment in the mutant cell line were chosen to continue this study. Subsequently, with dose-response curves, we were able to calculate the IC50 values of these compounds. Given the above findings, we will seek in the future to assess which of the six compounds are capable of activating and modulating wild-type p53, as well as to elucidate the molecular components involved in the process.

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Author

Raissa Eduardo dos Santos

Boa tarde, Daniela! Obrigada pela pergunta!
Pretendemos utilizar a  Pifitrina-alfa como um inibidor de p53 selvagem, onde poderemos observar se através da inibição de p53, veremos alguma diferença na atuação dos compostos. Além disso, queremos avaliar por Western Blotting, para observarmos se depois do tratamento com os compostos na presença e na ausência de Pifitrina, teremos alguma mudança nos níveis de p53 ou de proteínas ligadas diretamente a p53, como por exemplo, p21, que pode nos indicar algum efeito no ciclo celular.

Author

Raissa Eduardo dos Santos

Boa tarde, Denise! Muito obrigada pelo elogio e pela pergunta!

Sim, pretendemos testar os compostos em outros tipos de tumores que apresentam mutação em p53. E já estamos iniciando a triagem nas linhagens de câncer de ovário, A2780 (p53 selvagem) e OVCAR-3 (p53 mutante).

Author

Raissa Eduardo dos Santos

Boa tarde, Araci! Muito obrigada pelo elogio!

De acordo com as suas perguntas:

- Nós não testamos se os compostos possuem efeito anti-hemorrágico. Nosso projeto visa elucidar os mecanismo os quais estão envolvidos diretamente na p53. Esta abordagem pode ser usada em outro projeto, entretanto podemos pensar em futuramente realizar está verificação.

- Meus compostos são derivados mais especificamente da Menadiona (Vitamina K3), a qual possui atividade antitumural. Existem estudos que demonstram que a vitamina K foi capaz de induzir apoptose via ativação de p53 em linhagens de hepatocarcinoma (Smmc-7721). Desta forma, a partir de estudos anteriores, nós decidimos investir nesses compostos derivados da vitamina K. Além disso, meus compostos são uma segunda classe, a primeira classe é estudada pela minha co-orientadora no seu doutorado.

Muito obrigada pela pergunta! Um abraço!