RESUMEN
BACKGROUND: Cardiac glycosides are approved for the treatment of heart failure as Na+/K+ pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation. METHODS: Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry. RESULTS: At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression. CONCLUSION: Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.
Asunto(s)
Antineoplásicos/efectos adversos , Expresión Génica/efectos de los fármacos , Genes myc , Insuficiencia Cardíaca/etiología , Leucemia/genética , Lisina/metabolismo , Proscilaridina/efectos adversos , Acetilación , Antineoplásicos/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Relación Dosis-Respuesta a Droga , Epigénesis Genética/efectos de los fármacos , Perfilación de la Expresión Génica , Histonas/metabolismo , Humanos , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Modelos Biológicos , Proscilaridina/uso terapéutico , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
HPV-11 and HPV-6 are the etiological agents of about 90â% of genital warts (GWs). The intra-typic variability of HPV-11 and its association with infection persistence and GW development remains undetermined. Here, HPV infection in men (HIM) participants who had an HPV-11 genital swab and/or GW, preceded or not by a normal skin genital swab were analysed. Genomic variants were characterized by PCR-sequencing and classified within lineages (A, B) and sublineages (A1, A2, A3, A4). HPV-11 A2 variants were the most frequently detected in the genital swab samples from controls and in both genital swabs and GW samples from cases. The same HPV-11 variant was detected in the GW sample and its preceding genital swab. There was a lack of association between any particular HPV-11 variant and the increased risk for GW development.
Asunto(s)
Condiloma Acuminado/virología , Papillomavirus Humano 11/aislamiento & purificación , Adolescente , Adulto , Condiloma Acuminado/patología , Progresión de la Enfermedad , Genotipo , Papillomavirus Humano 11/clasificación , Papillomavirus Humano 11/genética , Papillomavirus Humano 11/fisiología , Humanos , Masculino , Filogenia , Adulto JovenRESUMEN
Background: Human papillomavirus type 6 (HPV-6) and HPV-11 are the etiological agents of approximately 90% of genital warts (GWs). The impact of HPV-6 genetic heterogeneity on persistence and progression to GWs remains undetermined. Methods: HPV Infection in Men (HIM) Study participants who had HPV-6 genital swabs and/or GWs preceded by a viable normal genital swab were analyzed. Variants characterization was performed by polymerase chain reaction sequencing and samples classified within lineages (A, B) and sublineages (B1, B2, B3, B4, B5). Country- and age-specific analyses were conducted for individual variants; odds ratios and 95% confidence intervals for the risk of GWs according to HPV-6 variants were calculated. Results: B3 variants were most prevalent. HPV-6 variants distribution differed between countries and case status. HPV-6 B1 variants prevalence was increased in GWs and genital swabs of cases compared to controls. There was difference in B1 and B3 variants detection in GW and the preceding genital swab. We observed significant association of HPV-6 B1 variants detection with GW development. Conclusions: HPV-6 B1 variants are more prevalent in genital swabs that precede GW development, and confer an increased risk for GW. Further research is warranted to understand the possible involvement of B1 variants in the progression to clinically relevant lesions.