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J Med Chem ; 65(20): 13681-13691, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36257066

RESUMO

Fatty acid synthase (FASN), a sole cytosolic enzyme responsible for de-novo lipid synthesis, is overexpressed in cancer but not in normal non-lipogenic tissues. FASN has been targeted, albeit no such inhibitor has been approved. Proton pump inhibitors (PPIs), approved for digestive disorders, were found to inhibit FASN with anticancer activities in attempting to repurpose Food and Drug Administration-approved drugs. Indeed, PPI usage benefited breast cancer patients and increased their response rate. Due to structural similarity, we thought that their metabolites might extend anticancer effects of PPIs by inhibiting FASN. Here, we tested this hypothesis and found that 5-hydroxy lansoprazole sulfide (5HLS), the end lansoprazole metabolite, was more active than lansoprazole in inhibiting FASN function and regulation of NHEJ repair of oxidative DNA damage via PARP1. Surprisingly, 5HLS inhibits the enoyl reductase, whereas lansoprazole inhibits the thioesterase of FASN. Thus, PPI metabolites may contribute to the lasting anticancer effects of PPIs by inhibiting FASN.


Assuntos
Inibidores da Bomba de Prótons , Neoplasias de Mama Triplo Negativas , Humanos , Lansoprazol/farmacologia , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Oxirredutases , Ácido Graxo Sintases/metabolismo , Sulfetos/farmacologia , Lipídeos
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