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Molecular markers of G1 or G2M checkpoints as targets of 5FU O,N-acetalic compounds with selective apoptotic antitumor activity against breast cancer cells

Juan Antonio Marchal, Houria Boulaiz, Macarena Perán, Pablo Álvarez, Fernando Rodríguez-Serrano, Antonio Martínez-Amat, Octavio Caba Pérez, Esmeralda Carrillo, Ana Rosa Rama, Consolación Melguizo, Fidel María Hita Contreras, Alberto Ramírez, Miguel Angel Gallo, Antonio Espinosa, Joaquín María Campos, Antonia Aránega


DOI: 10.4428/MMRR.p.201006002


Document Type: Poster


Date: Received 10th June 2010 16:01 UTC; Posted 10th June 2010 21:00 UTC


Subjects: Cancer, Cell therapy, Chemistry & Pharmacology


Tags:   breast cancer   apoptosis   molecular targets   cell cycle



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Abstract:
Uncontrolled cellular proliferation and/or alteration of apoptosis lead to breast cancer, as a consequence of the accumulation of genetic lesions, which give rise to alterations that activate proto-oncogenes and inactivate the tumour suppressor genes. In recent years, strategy in cancer therapy has been the use of high doses of toxic non-specific agents and to investigate a range of new agents that specifically target tumour-related molecules, in a variety of biological pathways. The development of new agents with tumour-specific mechanism of action on molecular targets that are responsible for cells transformation is one of main therapeutic strategies for improving chemotherapeutics. In this context, novel 5-fluorouracil (5-FU) derivatives possessing a broader spectrum of antitumor activity and fewer side effects than 5-FU, have been diligently sought in a number of laboratories. We have shown that benzannelated seven-membered O,N-acetals posses potent antiproliferative (in a micromolar range) and apoptotic activities in breast cancer cells. In order to elucidate its mechanisms of antitumour activity, we studied the effect of new drugs on the expression of molecular markers such cell cycle regulators (cyclin D1, p21, p27, p34,) and apoptosis-related proteins (Bcl-2 and p53) on MCF-7 human breast cancer cells. Our result showed that the high apoptotic activity induced by the novel compounds was due to inhibition of cyclin D or p34 expression, which implied the halting of the cell cycle in Go/G1 or G2 phases respectively and the non-entrance of tumour cells in mitosis. Moreover, DBDFU and 7MDFU compounds inhibited completely bcl-2 expression. In constrast, the most early and potent apoptotic compound DBOFU, increased cyclin D and p34 expression, decreased the members of Cip/Kip family p21 and p27 proteins. This compound had antitumour activity by selective induction of p53 activity in the p53-wild type MCF-7 breast cancer cells. In conclusion, our finding demonstrate the ability of benzannelated seven-membered O,N-acetals to target selective apoptotic or cell cycle checkpoints in breast cancer cells, suggesting its potential application as a new strategy for this type of cancer.
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