PURPOSE: Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined. METHODS: Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot. RESULTS: After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor. CONCLUSIONS: Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
PURPOSE: Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined. METHODS: Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot. RESULTS: After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor. CONCLUSIONS: Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
Authors: Axel Grothey; Eric Van Cutsem; Alberto Sobrero; Salvatore Siena; Alfredo Falcone; Marc Ychou; Yves Humblet; Olivier Bouché; Laurent Mineur; Carlo Barone; Antoine Adenis; Josep Tabernero; Takayuki Yoshino; Heinz-Josef Lenz; Richard M Goldberg; Daniel J Sargent; Frank Cihon; Lisa Cupit; Andrea Wagner; Dirk Laurent Journal: Lancet Date: 2012-11-22 Impact factor: 79.321
Authors: John M L Ebos; Christina R Lee; William Cruz-Munoz; Georg A Bjarnason; James G Christensen; Robert S Kerbel Journal: Cancer Cell Date: 2009-03-03 Impact factor: 31.743
Authors: Scott M Wilhelm; Christopher Carter; Liya Tang; Dean Wilkie; Angela McNabola; Hong Rong; Charles Chen; Xiaomei Zhang; Patrick Vincent; Mark McHugh; Yichen Cao; Jaleel Shujath; Susan Gawlak; Deepa Eveleigh; Bruce Rowley; Li Liu; Lila Adnane; Mark Lynch; Daniel Auclair; Ian Taylor; Rich Gedrich; Andrei Voznesensky; Bernd Riedl; Leonard E Post; Gideon Bollag; Pamela A Trail Journal: Cancer Res Date: 2004-10-01 Impact factor: 13.312