Withaferin-A induces apoptosis and autophagy in colorectal cancer cell lines via down-regulated expression of histone deacetylase 1.

La withaferina-A induce la apoptosis y la autofagia en líneas celulares de cáncer colorrectal mediante la regulación negativa de la expresión de la histona deacetilasa 1.

• Qiong Wang Qilu Hospital of Shandong University, Jinan, Shandong, China. https://orcid.org/0000-0003-1561-7559
• Caixia Li Department of Stomatology, Shandong Provincial People’s Hospital, Jinan, Shandong, China. https://orcid.org/0009-0003-4741-0429

DOI: https://doi.org/10.54817/IC.v67n1a06

Palabras clave: Apoptosis, Autofagia, Histona Desacetilasa 1, Focos de Criptas Aberrantes, Quimioprevención

Resumen

El cáncer colorrectal (CCR) sigue siendo la tercera malignidad más común en todo el mundo, y existe una necesidad urgente de preventivos o adyuvantes de baja toxicidad basados en mecanismos. Withaferin-A (WA), una lactona esteroide derivada de plantas, ha mostrado una amplia actividad antitumoral, pero su papel en el CRC y su interacción con reguladores epigenéticos, como la histona deacetilasa 1 (HDAC1), no están claros. Por lo tanto, se evaluó si WA suprime el crecimiento de CRC al regular la actividad de HDAC1 hacia abajo e inducir concomitantemente apoptosis y autofagia. Las células Caco2 y HT-29 se expusieron a WA 0–5 µM; la viabilidad, la formación de colonias y la migración se inhibieron marcadamente (IC₅₀ 0.70–1.52 µM). La citometría de flujo con Annexin-V/7-AAD, la tinción con MDC, la inmunofluorescencia de TEM y de LC3B mostraron que WA a 1 µM aumentó significativamente la apoptosis y el flujo autofágico, acompañados de la regulación descendente de HDAC1 y p62, la regulación ascendente de LC3B-II/I y un aumento en la relación Bax/ Bcl-2. La sobreexpresión de HDAC1 mediada por lentivirus revertió todos estos efectos, lo que confirma la dependencia de HDAC1. Para evaluar la relevancia traslacional, a ratones C57BL/6J de ocho semanas de edad se les administró primero el carcinógeno el carcinógeno de origen alimentario, 2-amino, 2-amino-3-metil-3H-imidazo[4,5-f]quinoline (100 mg/kg), cada dos días durante 3 semanas, para inducir focos de cripta aberrantes (ACF). A partir del día siguiente a la primera dosis de carcinógeno, los animales recibieron, adicionalmente, WA (2 mg/kg) o vehículo (aceite de maíz) por gavage cada dos días durante el mismo período. WA redujo el número macroscópico de ACF en más del 60%, restableció la expresión de LC3B y p62 asociada a HDAC1 a niveles normales y no mostró toxicidad ni en el peso corporal ni en el monitoreo general de la salud. Estos datos indican que WA ejerce una quimioprevención potente y de baja toxicidad contra la formación de lesiones de CRC mediante la inducción de apoptosis y autofagia dependientes de HDAC1, lo que respalda su desarrollo adicional como agente preventivo o adyuvante.

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