MilliporeSigma

A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth.

Cancers (2019-10-12)
Ludovica Lospinoso Severini, Deborah Quaglio, Irene Basili, Francesca Ghirga, Francesca Bufalieri, Miriam Caimano, Silvia Balducci, Marta Moretti, Isabella Romeo, Elena Loricchio, Marella Maroder, Bruno Botta, Mattia Mori, Paola Infante, Lucia Di Marcotullio
ABSTRACT

: Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Histone Deacetylase 1 (HDAC1) antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution