ABSTRACT
A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Subject(s)
Female , Male , Humans , Cisplatin/pharmacology , Disulfiram/pharmacology , Testicular Neoplasms/drug therapy , Fanconi Anemia/drug therapy , Alcoholism/drug therapy , Drug Resistance, Neoplasm , Cell Line, Tumor , Substance Withdrawal Syndrome/drug therapy , Apoptosis , Antineoplastic Agents/therapeutic use , Cell ProliferationSubject(s)
Adjuvants, Immunologic/pharmacology , Animals , Chelating Agents/pharmacology , Disulfiram/pharmacology , Ditiocarb/pharmacology , Drug Resistance , Glutathione/metabolism , Humans , Leishmania donovani/metabolism , Leishmania major/metabolism , Leishmania tropica/metabolism , Leishmaniasis/drug therapy , Nitric Oxide/metabolism , Oxidative Stress , ATP Binding Cassette Transporter, Subfamily B/metabolismABSTRACT
Se prepara un estudio analítico sobre los efectos farmacológicos y toxicológicos del Disulfuro de Tetraetiltiuram (Disulfiram), el cual es utilizado en la terapéutica del alcoholismo crónico, por su efecto antabuse, uso que se remonta a más de 30 años. Posteriormente, se presentan dos casos de pacientes intoxicadas con disulfiram, y las ingresaron en el Servicio de Emergencia de Adultos del HUC; en un lapso de tiempo de 10 meses. De dos casos, uno tuvo un desenlace fatal