SB431542 [Neurosurgery Wiki]

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====== SB431542 ======

SB431542 is a selective and potent inhibitor of the TGF-β/Activin/NODAL pathway that inhibits ALK5 (IC₅₀ = 94 nM), ALK4 (IC₅₀ = 140 nM), and ALK7, but does not inhibit the BMP type I receptors ALK2, ALK3, and ALK6. 

While [[dopamine agonist]]s are a primary method of therapeutic treatment for [[Lactotroph adenoma]], the rate of resistance to these [[drug]]s continues to increase each year. During previous long-term clinical investigations, Hu et al., from Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, [[Guangzhou]], [[China]], found that partial resistant [[prolactinoma]]s exhibited significantly more fibrosis than did sensitive [[adenoma]]s, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III [[collagen]]s. Since [[TGF-β1]] is the key factor in the initiation and development of tissue fibrosis, including in the [[pituitary]], in this study, they aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using [[immunochemistry]] and [[western blot]]ting, they found that the [[TGF-β1]]/[[Smad3]] [[signaling pathway]]-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. [[In vitro]], TGF-β1 stimulation promoted collagen expression in normal [[HS27]] [[fibroblast]]s. Furthermore, the sensitivity of rat prolactinoma [[MMQ cell]]s to [[bromocriptine]] decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor [[SB431542]] counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of [[prolactinoma]]s. These results indicate that [[SB431542]] may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of [[prolactinoma]]s
((Hu B, Mao Z, Jiang X, He D, Wang Z, Wang X, Zhu Y, Wang H. Role of
[[TGF-β1]]/[[Smad3]]-mediated [[fibrosis]] in drug resistance mechanism of [[prolactinoma]].
Brain Res. 2018 Jul 26. pii: S0006-8993(18)30408-6. doi:
10.1016/j.brainres.2018.07.024. [Epub ahead of print] PubMed PMID: 30055965.
)).