Curcumol and Oxaliplatin exhibit synergistic anti-tumor effect in colorectal cancer by co-targeting the KPNA2/c-Myc axis

Objectives Curcumol is a natural product that has been demonstrated to exert antitumor effects in many tumor types. Oxaliplatin is one of the chemotherapeutic agents commonly employed in the treatment of colorectal cancer (CRC). In this study, we aimed to investigate the synergistic antitumor role of Curcumol and Oxaliplatin in CRC and explore the potential mechanisms. Methods The synergistic antitumor efficacy of Curcumol and Oxaliplatin in CRC cells was assessed by using CCK-8, flow cytometry, and colony formation assays. The impact of KPNA2 knockdown on cell proliferation was tested in vitro and in vivo . HCT-116 cell line-derived xenograft (CDX) mouse model was established to explore the synergistic antitumor efficacy of Curcumol and Oxaliplatin in CRC. Results Curcumol inhibited CRC cell viability, induced apoptosis, and suppressed colony formation. KPNA2 was significantly overexpressed in CRC tissues compared with normal controls (p<0.001). High KPNA2 expression significantly correlated with shorter overall survival (p<0.05). Genetic knockdown of KPNA2 inhibited cell proliferation and clonogenicity in vitro and attenuated xenograft tumor growth in vivo . Curcumol and Oxaliplatin exhibited synergistic cytotoxicity against CRC cells (Combination index <0.9). Mechanistically, both Curcumol and KPNA2 knockdown led to a marked reduction in the oncoprotein of c-Myc. The combination of Curcumol and Oxaliplatin decreased KPNA2 and c-Myc expression more significantly compared with either single-drug control. The CDX mouse model showed that Curcumol/Oxaliplatin combination therapy exhibited superior tumor growth suppression compared with monotherapies (p<0.01). Conclusions Our study suggested that Curcumol combined with Oxaliplatin exerts significant antitumor activity in CRC by targeting the KPNA2/c-Myc axis.