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Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition

AuthorsRamírez de Molina, Ana; Cueva, Ana de la; Machado-Pinilla, R. ; Rodriguez-Fanjul, V. ; Gómez del Pulgar, Teresa; Cebrián, Arancha; Perona Abellón, Rosario ; Lacal, Juan Carlos
Issue Date2012
PublisherBentham Science Publishers
CitationCurrent Cancer Drug Targets 12(6): 617-624 (2012)
AbstractWe have analyzed the response of primary cultures derived from tumor specimens of non small cell lung cancer (NSCLC) patients to choline kinase α (ChoK α) inhibitors. ChoK α inhibitors have been demonstrated to increase ceramides levels specifically in tumor cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumors. NSCLC cells with acquired resistance to ChoK α inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKα inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKα specific inhibition and represents a model for combinatorial treatments of ChoK α inhibitors and ASAH1 inhibitors. Considering that ChoK α inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development. © 2012 Bentham Science Publishers.
Identifiersdoi: 10.2174/156800912801784811
issn: 1568-0096
e-issn: 1873-5576
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