Definição de alvos moleculares em diferenciação, morte e resistencia de celulas tumorais / Defenition of molecular targets indifferentiation, death and resisteance in cancer cells

AUTOR(ES)

Karla Cristiane de Souza Queiroz

DATA DE PUBLICAÇÃO

2007

RESUMO

Cancer therapy efficiency, under several aspects, even with the progress of “pharmacotechnology”, remains as a challenge for the medicine. According to this factor, new agents that act on specific target, present low side-effects and prevent cancer cells “escaping” from death induction, are extremely desirable. In this work, 3 aspects of antitumoral property of riboflavin were evaluated: apoptosis induction of prostate cancer cells, leukaemic cells differentiation and increase of intracellular bioavailability of chemotherapic (mitoxantrone). Under these 3 aspects, and by signal transduction approach, we identified molecular mediators responsible for antitumoral activity of riboflavin. The action of irradiated riboflavin on prostate cancer cells was dependent on PI3K inhibition. Interestingly, we also observed a potential inhibitory action of metastasis, as demonstrated by the inhibition of metalloproteinases 2 and 9 and decreasing of angiogenesis by downregulation of VEGF. In relation to leukaemic cells differentiation we demonstrated the involvement of TNFR1, as well as cyclin D, JNK, Src kinase and protein tyrosine phosphatases SHP2 and PTP!. Therefore, proteins with different cellular localizations were affected culminating in decreasing of cell proliferation, maintaining cell survival, cell cycle arrest and cytoskeleton rearrangement, crucial metabolic effects for the occurrence of differentiation process. This work also demonstrated the applicability of Pepchip technique for identifying the differences between 2 erytroblastic leukaemia cell lines, K562 and Lucena. Other interesting approach, in this work, was the use of riboflavin for improving chemotherapic cellular bioavailability and the strategical use of protein phosphatase inhibitors for reverting tumor cells resistance. According to our findings, this work spotlights the novel function of the vitamin B2 as an antitumoral agent.

ASSUNTO(S)

cellular signal transduction apoptose celulas - diferenciação neoplasms transdução de sinal celular apoptosis cell differentiation tumores

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