Discovery of a potent hedgehog pathway inhibitor capable of activating caspase8-dependent apoptosis.
J Pharmacol Sci
; 137(3): 256-264, 2018 Jul.
Article
en En
| MEDLINE
| ID: mdl-30064819
ABSTRACT
Aberrant activation of Hedgehog (Hh) signaling is associated with the development of numerous human cancers. Vismodegib is the first Hh inhibitor approved for anti-cancer therapy by targeting Smoothened (SMO), a critical regulator of the Hh pathway. However, acquisition of drug resistance to vismodegib occurs overtime. Apoptosis is a prevalent form of programmed cell death that is executed by caspases. Induction of tumor cell apoptosis represents an attractive therapeutic strategy to eliminate tumor cells. To explore new Hh antagonists with apoptosis-inducing activity, we screened a set of â¼300 potential SMO antagonists with novel scaffold structures. Hh003 was found to induce caspase-dependent apoptosis while vismodegib did not activate apoptotic response in human colon and pancreatic cancer cells. Compared to vismodegib, Hh003 exerted similar inhibitory effects on the Hh pathway. Hh003 could induce caspase8 activation and the silence of caspase8 significantly inhibited Hh003-induced apoptosis. Remarkably, Hh003 showed stronger inhibitory effects on the formation of tumor colonies in vitro and colorectal tumor growth in vivo than vismodegib. These findings suggest that Hh003 exerts enhanced anti-tumor effects by activating caspase8-dependent apoptosis compared to vismodegib. The combined property of Hh inhibition and apoptosis induction of Hh003 presents great potential for the development of novel anti-cancer therapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Transducción de Señal
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Apoptosis
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Neoplasias del Colon
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Caspasa 8
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Proteínas Hedgehog
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Anilidas
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Pharmacol Sci
Asunto de la revista:
FARMACOLOGIA
Año:
2018
Tipo del documento:
Article