Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition.
2012
We have analyzed the response of primary cultures derived from tumor specimens of non small cell lung
cancer (NSCLC) patients to choline kinase α (ChoKα) inhibitors. ChoKα 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 ChoKα 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 ChoKα inhibitors and ASAH1
inhibitors. Considering that ChoKα 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.
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