Acid Ceramidase as a Chemotherapeutic Target to Overcome Resistance to the Antitumoral Effect of Choline Kinase α Inhibition

A.      Ramirez de Molina; A.      de la Cueva; R.      Machado-Pinilla; V.      Rodriguez-Fanjul; T.      Gomez del Pulgar; A.      Cebrian; R.      Perona; J.      C. Lacal

Abstract

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.

Keywords: Acid ceramidase, choline kinase, lung cancer, resistance, alkaline ceramidase, neutral ceramidase, complementary deoxyribonucleic acid, choline kinase α, ChoKα inhibitor, D-erythro-2-(N-myristoylamino)-1-phenyl-1- propanol, Dulbecco’s modified Eagle's medium, Nutrient Mixture F12 Ham, Fetal Bovine Serum, N-Oleoyl ethanolamine, non small cell lung cancer