This study aimed to elucidate the antitumor activity of norcantharidin (NCTD) against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were examined by MTS and flow cytometry. Caspase-3, -8, and -9 activities were detected with a colorimetric caspase protease assay. Apoptotic proteins—including PARP, cyclin D1, Bcl-2 family proteins, XIAP, and cIAP I—were studied by western blot. The phosphoinositide 3 kinase (PI3K) inhibitor LY294002 was used to investigate the involvement of the PI3K/Akt signaling pathway. In vivo studies were performed using Z138 cell xenografts in nude mice. NCTD inhibited proliferation and induced apoptosis of Z138 and Mino cells, both in vitro and in vivo. PI3Kp110α and p-Akt expressions were downregulated by NCTD treatment. NCTD downregulated NF-κB activity by preventing NF-κB phosphorylation and nuclear translocation. This effect was correlated with the suppression of NF-κB-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP. This phenomenon was blocked by the PI3K inhibitor LY294002. Our results demonstrated that NCTD can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the PI3K/Akt/NF-κB signaling pathway. NCTD may have therapeutic and/or adjuvant therapeutic applications in the treatment of MCL.
Norcantharidin (NCTD), the demethylated analog of the Chinese medicine cantharidin, exhibits anti-myeloma activity by inactivating nuclear factor-κB (NF-κB), which is implicated in multiple myeloma (MM) cell survival and resistance to bortezomib (BTZ). We investigated whether NCTD could potentiate the anti-tumor activity of BTZ in MM. NCTD inhibited the proliferation of MM cells and potentiated the anti-myeloma effects of BTZ by down-regulating IKKα and p-IκBα, which induced the accumulation of IκBα and inhibited the constitutive activation of NF-κB. This effect was correlated with the suppression of NF-κB-regulated gene products. Furthermore, a chemotherapy-potentiating effect of NCTD on BTZ was also observed in vivo. Our study demonstrated that NCTD and BTZ exhibit significant therapeutic effects on MM through the NF-κB signal pathway in vitro and in vivo. Future studies will investigate the combined effects of NCTD and BTZ in patients with MM.
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