The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 10; p. 2454
• Main Authors: Yu, Cheng-Chan, Huang, Sung-Ying, Chang, Shu-Fang, Liao, Kuan-Fu, Chiu, Sheng-Chun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.05.2020; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Angiogenesis; Antineoplastic Agents - pharmacology; Apoptosis; BEZ235; Cancer therapies; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Cell adhesion & migration; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; combination therapy; Combined treatment; Drug Combinations; Drug dosages; Drug Synergism; Enzyme inhibitors; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Gelatin; Gelatinase B; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatocellular carcinoma; Humans; Imidazoles - pharmacology; Inhibitory Concentration 50; Kinases; Liver cancer; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Mesenchyme; Metalloproteinase; metastasis; Phenylurea Compounds - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI3K/Akt/mTOR pathway; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Proteinase; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyridines - pharmacology; Quinolines - pharmacology; regorafenib; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Targeted cancer therapy; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Vimentin; Vimentin - genetics; Vimentin - metabolism; BEZ235; combination therapy; regorafenib; metastasis; PI3K/Akt/mTOR pathway; hepatocellular carcinoma
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25102454

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines ( = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.