Recurrence and metastasis remain major obstacles to the successful treatment of hepatocellular carcinoma(HCC),and inhibition of HCC metastasis is the key to prolonging the overall survival time and improving the prognosis of patients with hepatocellular carcinoma.Tumor metastasis is associated with the gradual loss of epithelioid cell features and the increase of mesenchymal cell features in tumor cells,and the inhibition of epithelio-mesenchymal transition(EMT)of tumor cells is an effective strategy to reduce tumor metastasis.In addition,more and more studies have shown that the tumor microenvironment is another important reason for mediating local invasion and spread of tumors.Immune cells are an important component of the tumor microenvironment,the most abundant of which are macrophages.The special physiological structure of the liver is particularly conducive to the infiltration of tumor-associated macrophages(TAMs)in HCC,and HCC cells and macrophages communicate with each other through the secretion of various cytokines,which together promote the malignant development of the tumor.HCC treatment is susceptible to drug resistance,and a large amount of clinical therapeutic evidence has shown that the occurrence of drug resistance to chemotherapeutic,targeted,and immunotherapeutic drugs is associated with an increase in infiltration of tumor M2-like TAMs.Therefore,inhibition of macrophage M2-like polarization is an effective synergistic anti-HCC immunotherapy.The successive discovery of antitumor immunotherapeutic activity of platinum-based metallodrugs such as oxaliplatin has made anti-tumor metal complexes with chemo-immunotherapeutic activity a hot research topic.However,excessive cytotoxicity of platinum-based chemotherapeutic drugs causing myelosuppression and lymphocytopenia will lead to immunosuppression,which is detrimental to the treatment of tumors.And the combination of small-dose cytotoxic chemotherapeutic drugs and immunotherapeutic drugs may even exert efficient and synergistic anticancer activities when appropriate combination regimens are used.For these reasons,down-regulation of cytotoxicity is a prerequisite for improving the immunotherapeutic activity of metal complexes.With the relatively low cytotoxicity of lanthanide metal complexes and the synergistic effect of lanthanide metals on the inhibition of M2-like polarization of macrophages,it is feasible to screen for chemo-immunotherapeutic activity of anti-HCC complexes among lanthanide complexes with low cellular cytotoxicity.Oxoaporphine alkaloids are aporphine alkaloids with a 7-carbonyl structure that have a variety of biological activities.It is easy to combine them with metal ions via chelate coordination to form bifunctional complexes for their pyridine nitrogen and carbonyl oxygen donor planar structure.In this study,synthesized and characterized an oxoaporphine(L)Pr(III)complex(Pr L3(NO3)3)and found that it inhibits HCC progression and metastasis by disrupting HCC cell–macrophage crosstalk.On the one hand,in HCC cells,Pr L3(NO3)3inhibited nuclear factor-kappa B(NF-κB)nuclear translocation and downregulated the expression of Snail and chemokine(C-C motif)ligand 2(CCL2),thereby affecting HCC cell migration and invasion and reducing chemotaxis to inflammatory monocytes.On the other hand,in macrophages,Pr L3(NO3)3 activated the NF-κB pathway and inhibited the AMP-activated protein kinase(AMPK)pathway,suppressing M2 polarization and synergistically inhibiting HCC cell proliferation,migration,and invasion.This is the first finding of a lanthanide complex exerting regulatory effects on both tumors and tumor-associated macrophages,providing a new strategy for the design and development of antitumor metal complexes for chemoimmunotherapy.Constitutive activation of NF-κB is the main feature that distinguishes HCC cells from normal cells,and many studies have shown that NF-κB is an effective target for anti-HCC.Since immune cells also express NF-κB and its activation facilitates the activation of immunity,pan-inhibition of NF-κB impairs immune cell function,which is not conducive to tumor therapy and renders antitumor drugs targeting NF-κB clinically ineffective.In this study,it was found that Pr L3(NO3)3 inhibited HCC cell NF-κB activity and enhanced macrophage NF-κB activity by promoting Rel A/p65 Ser536 phosphorylation,facilitating the activation of tumor immunity.This study provides important insights to promote the use of NF-κB inhibitors in tumor therapy. |