Data from Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism

• DOI: 10.1158/0008-5472.c.6497139.v1
• Publication Date: 2023-03-30T23:19:02Z
• Authors: Anna Maria Giamma...; Angela Maselli; Andrea Casagrande; Lucrezia Gambardella; Angelo Gallina; Massimo Spada; Antonello Giovann...; Enrico Proietti; Walter Malorni; Marina Pierdominici
• Keywords: Caspase 8

<div>Abstract<p>The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due the development resistance apoptosis. Pyrimethamine belongs group antifolate drugs, in addition antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, examined <i>in vitro</i> effects on apoptosis, cell cycle distribution, proliferation lines. The vivo</i> antitumor potential was evaluated severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our indicate that pyrimethamine, when used at clinically relevant concentration, induced apoptosis cells via activation cathepsin B caspase cascade (i.e., caspase-8 caspase-9) subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, marked inhibition growth an S-phase arrest. Results obtained SCID mice, injected s.c. with treated indicated significant inhibitory effect tumor growth. In conclusion, our results suggest pyrimethamine-induced may be considered as multifaceted process, different inducers or regulators simultaneously implicated, permitting death defects bypassed overcome. On these bases, hypothesize could represent interesting candidate for treatment melanoma. [Cancer Res 2008;68(13):5291–300]</p></div>