EXPLORING THE ANTI-TUMOR EFFICACY OF COMBINATION THERAPY WITH INHIBITORS TARGETING THE INSULIN-LIKE GROWTH FACTOR (IGF) AND PI3K/AKT/MTOR SIGNALING PATHWAYS FOR HEPATOCELLULAR CARCINOMA (HCC)

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Abstract

Background

The IGFR signaling pathway plays important roles in carcinogenesis and drug resistance of many cancers, including HCC, but inhibitors targeting the IGF signaling pathway showed limited therapeutic efficacy. This study explored the efficacy of combining inhibitors targeting the IGF and PI3K/AKT/mTOR signaling pathways in HCC.

Methods

HCC cell lines tested included Hep3B, Huh7, and PLC5. The MTT agents tested included NVP-AEW541 (IGF receptor kinase inhibitor, Novartis), MK2206 (Akt inhibitor, MSD), BEZ235 (PI3K/mTOR inhibitor, Novartis), and RAD001 (mTOR inhibitor, Novartis). The potential synergistic antitumor effects were tested by MTT assay and median dose effect analysis in vitro and by xenograft models in vivo. Apoptosis was analyzed by flow cytometry and western blotting. The activity of pertinent signaling pathways and expression of apoptosis-related proteins were measured by western blotting and by an apoptosis protein array (Proteome ProfilerTM, R&D Systems).

Results

Synergistic growth-inhibitory and apoptosis-inducing effects in HCC cells were found most prominently in NVP-AEW541/ MK2206 combination, followed by NVP-AEW541/BEZ235 combination. These synergistic anti-tumor effects correlated with a more sustained inhibition of Akt and 4EBP-1 phosphorylation. Potential downstream mediators identified by the apoptosis array included survivin and clapsin. The synergistic anti-tumor effects of NVP-AEW541/MK2206 and NVP-AEW541/BEZ235 combinations were confirmed in vivo by xenograft models, with acceptable toxicity profiles.

Conclusions

Combination therapy of IGF receptor inhibitors with inhibitors targeting the PI3K/AKT/mTOR pathway may have therapeutic efficacy in HCC (supported by grants NHRI-EX100-9911BC, DOH100-TD-B-111-001, and NSC 100-2314-B-002-058-MY3).

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