Curcumol Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells

Abstract

Background: Lenvatinib is an important molecular target drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the application of molecular targeted therapies for HCC also faces some challenges. Cumulative evidence has also shown that curcumol is a potential anti-HCC drug. Curcumol can be used as a chemosensitizer to enhance the antitumor effect of chemotherapeutic drugs. The purpose of our study is to explore the effect of curcumol combined with lenvatinib on HCC. Methods: The antitumor effects of curcumol or/and lenvatinib on Huh 7 cells of the HCC cell line were examined using the cell counting kit-8 (CCK-8) assay, colony formation assay, and transwell assay. For in vivo investigation, the effect on subcutaneous growth was also determined in nude mice. Changes in autophagy were determined by transmission electron microscope (TEM). Protein levels of apoptotic-related factors, epithelial mesenchymal transition (EMT)-related factors, autophagy factors, and Ncadherin and janus tyrosine kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) were examined by Western blot. Results: In this study, we found that curcumol or lenvatinib could promote HCC cell apoptosis in vitro and inhibit the growth of HCC tumors in vivo (curcumol or lenvatinib group compared with control group, p < 0.05). While combination with curcumol treatment could improve the effect of lenvatinib on promoting cell apoptosis of HCC in vitro and inhibiting the growth of HCC tumors in vivo (combination group compared with lenvatinib group, p < 0.05). Curcumol combined with lenvatinib could induce more autolysosome formation detected by TEM. Mechanically, curcumol or lenvatinib could increase the expression of Bcl-2-associated X protein (Bax), E-cadherin, UNC-51-like kinase 1 (ULK), and microtubule-associated protein 1 light chain 3 (LC3B) II/I, whereas it reduced the expression of B-cell lymphoma-2 (Bcl-2), JAK2/STAT3 (curcumol or lenvatinib group compared with control group, p < 0.05). Furthermore, combined with curcumol treatment could increase the expression of Bax, E-cadherin, ULK, and LC3B II/I, whereas it reduced the expression of Bcl-2, N-cadherin, and JAK2/STAT3 (combination group compared with lenvatinib group, p < 0.05). These findings suggest that curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells. Conclusion: Curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.