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UC Irvine, Italian researchers create first inhibitor for enzyme linked to melanoma, lung and prostate cancers

Novel compound seen as enhancing the cancer-killing power of anti-tumor drugs

UC Irvine professor Daniele Piomelli, Louise Turner Arnold Chair in the Neurosciences

Irvine, Calif., Nov. 20, 2014 — Recent studies showing acid ceramidase (AC) to be upregulated in melanoma, lung and prostate cancers have made the enzyme a desired target for novel synthetic inhibitor compounds. This week in Angewandte Chemie, a top journal in chemistry, scientists with UC Irvine School of Medicine and the Italian Institute of Technology describe the very first class of AC inhibitors that may aid in the efficacy of chemotherapies.

AC, which is encoded by the ASAH1 gene, plays an important role in the regulation of cell fate, setting the balance between pro-aging/death and pro-life signals. Mutations in the ASAH1 gene have been associated with
a lysosomal storage disorder called Farber disease and with spinal muscular atrophy.

In their Angewandte Chemie study, UC Irvine's Daniele Piomelli — the Louise Turner Arnold Chair in the Neurosciences — and colleagues present a potent and systematically active small-molecule inhibitor of intracellular AC.

In in vivo studies, the team found that inhibiting AC with their novel compound tilts the balance between pro-aging/death and pro-life chemical signals, favoring the former at the expense of the latter.

"We hope that AC inhibitors may be one day used as 'chemosensitizers' — drugs that enhance the cancer-killing power of anti-tumoral drugs," said Piomelli, a professor in the Department of Anatomy & Neurobiology who also is affiliated with UC Irvine Chao Family Comprehensive Cancer Center.

"The new chemical scaffold we published is a promising starting point for the development of novel therapeutic agents, and we aim to pursue its further pharmaceutical development."

Daniela Pizzirani, Anders Bach, Natalia Realini, Andrea Armirotti, Luisa Mengatto, Inga Bauer, Stefania Girotto, Chiara Pagliuca, Marco De Vivo, Maria Summa, Alison Ribeiro of the Italian Institute of Technology in Genoa contributed to the research, which received support from the Carlsberg Foundation. UC Irvine and the Fondazione Istituto Italiano di Tecnologia have filed for patent protection of the new class of molecules.