Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studies demonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression induced NF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdown suppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part, through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b-NF-kB axis in ovarian cancer.
Vascular endothelial growth factor (VEGF) is the key molecule mediating tumor growth and malignant ascites formation. We recently reported that, in an end stage OVCAR-3 xenograft model, albendazole (ABZ) suppresses ascites formation, but not tumor growth. Hence, in the present study, we assessed the effect of ABZ on in vitro OVCAR-3 cell proliferation plus in vivo tumor growth, however, initiating ABZ treatment at mid stage (3 weeks post cell inoculation) rather than end stage disease. Here, ABZ treatment led to potent inhibition of cell proliferation, VEGF suppression, complete inhibition of ascites formation and most strikingly arrest of tumor growth.
BackgroundEmerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α.MethodIn vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR.ResultsIn vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ.ConclusionThese results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis.
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