Sorafenib inhibits p38α activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response

• DOI: 10.4161/cbt.22254
• Publication Date: 2012-12-10T16:10:07Z
• Authors: Valentina Grossi; Micaela Liuzzi; Stefania Murzilli; Nicola Martelli; Anna Napoli; Giuseppe Ingravallo; Alberto Del Rio; Cristiano Simone
• Keywords: Niacinamide; 0301 basic medicine; Caspase 3; Pyridines; Phenylurea Compounds; Transplantation, Heterologous; Imidazoles; Mice, Nude; Apoptosis; Drug Synergism; Sorafenib; 3. Good health; Mitogen-Activated Protein Kinase 14; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Female; Colorectal Neoplasms; Neoplasm Transplantation; Signal Transduction

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.