Synergistic antitumor effect of all-trans retinoic acid on regorafenib-treated human colon cancer cell lines via modulation of the AMPK/VEGF/ERK/NFKB/caspase-3 signaling axis

Abstract Purpose Colon cancer is the second most common cause of cancer-related death worldwide. Angiogenesis mediated by vascular endothelial growth factor (VEGF) plays important roles in cancer progression, and activated mitogen protein kinase (AMPK) has also been shown to exert both positive and negative effects on angiogenesis and different oncogenic signaling pathways. The multikinase inhibitor regorafenib prevents the activation of numerous kinases involved in angiogenesis, proliferation, and metastasis. All-trans retinoic acid (ATRA) has also been demonstrated to inhibit the growth and the development of different types of tumors. This study aims to assess the antitumor effects of ATRA in regorafenib-treated human colon cancer cell lines and investigate the molecular mechanism mediating these effects. Methods The levels of VEGF, AMPK, extracellular signalregulated protein kinase 1 (ERK1), and nuclear factor kappa B (NF-κB) were analyzed using enzyme-linked immunosorbent assay, and caspase-3 activity was assessed colorimetrically. Results ATRA potentiated AMPK and caspase-3 activities and reduced the levels of VEGF, ERK1, and NF-κB levels in regorafenib-treated human colon cancer cell lines. Conclusion ATRA exerted synergistic antiproliferative, antiangiogenic, and proapoptotic effects on regorafenib-treated colorectal cancer cells by modulating the AMPK/VEFG/ERK/NF-κB/caspase-3 signaling axis.