title: Sorafenib inhibits p38α activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response.
abstract: In the search for new strategies to efficiently fight colorectal cancer, efforts are being increasingly focused on targeting regulatory signaling pathways involved in cancer-specific features. As a result, several studies have recently addressed the therapeutic potential of molecularly-targeted drugs capable of inhibiting the activity of protein kinases involved in relevant signaling cascades. Here we show that simultaneous inhibition of the DFG-in and DFG-out conformations of p38α by means of type-I and type-II inhibitors is beneficial to impair more efficiently its kinase activity. Moreover, we found that SB202190 (type-I) and sorafenib (type-II) synergize at the molecular and biological level, as co-treatment with these compounds enhances tumor growth inhibition and induction of apoptosis both in colorectal cancer cell lines and animal models. These results support the need to reconsider sorafenib as a therapeutic agent against colorectal cancer and provide new insights that underline the importance to elucidate the activity of protein kinase inhibitors for the treatment of colorectal carcinoma.
authors.affiliation: Cancer Genetics Laboratory, IRCCS S. de Bellis, Castellana Grotte, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.forename: Micaela
authors.initials: M
authors.lastname: Liuzzi
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.forename: Nicola
authors.initials: N
authors.lastname: Martelli
authors.forename: Anna
authors.initials: A
authors.lastname: Napoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ingravallo
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014183:Transplantation, Heterologous
chemical_list: D007093:Imidazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048308:Mitogen-Activated Protein Kinase 14; D053148:Caspase 3; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole