AG-1024 Sensitizes Sorafenib-Resistant Hepatocellular Carcinoma Cells to Sorafenib via Enhancing G1/S Arrest

Abstract

Purpose The frequency in resistance to sorafenib accounts for the grim prognosis of advanced hepatocellular carcinoma (HCC). In the present study, we explore the anti-cancer efficacy of co-administration of sub-toxic AG-1024 with sorafenib in HCC cells to enhance the sensitivity of these cells to sorafenib. Materials and Methods Two acquired sorafenib-resistant HCC cells, SNU-sora-5 and SK-sora-5, were established and verified. The MTT assay, colony formation assay, cell morphology detection and flow cytometric analysis were then used to determine the anti-tumor effects of the co-administration of sub-toxic AG-1024 and sorafenib. Finally, the potential molecular mechanism was preliminarily examined. Results Compared to parental cell lines, the acquired sorafenib-resistant cell lines, SNU-sora-5 and SK-sora-5, were more resistant to sorafenib. Sub-toxic AG-1024 markedly enhanced sorafenib-mediated cell inhibition in acquired sorafenib-resistant HCC strains, with a reversal index (RI) of 4.64 in SNU-sora-5 and 4.58 in SK-sora-5 cell lines. Moreover, co-administration of sub-toxic AG-1024 and sorafenib exerted dramatic cytotoxicity compared with sorafenib alone in the intrinsic sorafenib-resistant HCC-LM3 cells. In contrast to high-dose sorafenib, sub-toxic AG-1024 combined with sorafenib had less impact on apoptosis while significantly enhancing G1/S arrest via activation of the mTOR/p21 signaling pathway. The more, pharmacological inhibition of mTOR activity by inhibitor Palomid 529 significantly antagonized the synergistic anti-cancer effects of AG-1024 and sorafenib in HCC cells. Conclusion The current findings indicate that sub-toxic AG-1024 may be a promising therapeutic agent in enhancing the sensitivity in HCC cells to sorafenib, bringing hope to HCC patients refractory to sorafenib treatment.

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“…Sorafenib is a multityrosine kinase inhibitor used to treat HCC ( 34 ). However, its sensitivity appears in only 30% of the patients, and within 6 months, sorafenib resistance is acquired in HCC ( 35 ).…”

Synthesis of Sorafenib−Ruthenium Complexes, Investigation of Biological Activities and Applications in Drug Delivery Systems as an Anticancer Agent

“…The cells were incubated at 37 °C under an atmosphere of 5% CO 2 and 95% humidity. HepG2-SR cells were selected according to the short-term sorafenib exposure protocol . The cells were exposed to sorafenib at concentrations of 1, 2, and 4 μM for 72 h in gradual increments.…”

“…HepG2-SR cells were selected according to the short-term sorafenib exposure protocol. 41 The cells were exposed to sorafenib at concentrations of 1, 2, and 4 μM for 72 h in gradual increments. At each stage, surviving cells were plated in sorafenib-free medium.…”

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

“…Among these differently expressed genes, resistant cells showed enrichment of FGF and insulin-like growth factor (IGF) pathways [155]. A combination of sorafenib with AG-1024 (anti-IGF1R) provided significantly higher anti-cancer effects in cells resistant to sorafenib [156]. Moreover, in sorafenib-resistant HCC cells, an activated positive loop between EGFR and Kruppel-like factor 4 (KLF4) has been detected.…”