Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines.
Endocr Relat Cancer
; 14(3): 839-45, 2007 Sep.
Article
em En
| MEDLINE
| ID: mdl-17914112
ABSTRACT
The introduction of paclitaxel into multimodal therapy for anaplastic thyroid carcinoma has failed to improve overall survival. Toxicity rules out the high doses required, especially in older patients. The search for strategies to enhance paclitaxel antineoplastic activity and reduce its side effects is thus advisable. The study aimed to determine whether the histone deacetylase (HDAC) inhibitor valproic acid (VPA) improves the anticancer action of paclitaxel and elucidate the mechanisms underlying the effects of combined treatment. We examined the effect of VPA on the sensitivity to paclitaxel of two anaplastic thyroid carcinoma cell lines (CAL-62 and ARO), and the ability of the drug to determine tubulin acetylation and enhance paclitaxel-induced acetylation. The addition of as little as 0.7 mM VPA to paclitaxel enhances both cytostatic and cytotoxic effects of paclitaxel alone. Increased apoptosis explains the enhancement of the cytotoxic effect. The mechanism underlying this effect is through inhibition of HDAC6 activity, which leads to tubulin hyperacetylation. The results suggest a mechanistic link between HDAC6 inhibition, tubulin acetylation, and the VPA-induced enhancement of paclitaxel effects, and provide the rationale for designing future combination therapies.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Acetiltransferases
/
Tubulina (Proteína)
/
Neoplasias da Glândula Tireoide
/
Carcinoma
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Ácido Valproico
/
Paclitaxel
/
Apoptose
Idioma:
En
Revista:
Endocr Relat Cancer
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Itália