Inhibition of NFκB Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models

Abstract

Whether or not inhibition of NFB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of IB␣ and activity of NFB between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of IB␣ and activity of NFB in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of IB␣ and activity of NFB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of IB␣ and activation of NFB and less marked inhibition of the phosphorylation of IB␣ and activation of NFB by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NFB activity either by treatment with the IB␣ phosphorylation inhibitor (BAY 11-7085) or a specific NFB nuclear translocation inhibitor (SN-50) or by transfection of p50⌬NLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of IB␣ phosphorylation and NFB activity and the cisplatininduced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NFB inhibitor should increase the therapeutic efficacy of cisplatin.The sensitivity of cells to chemotherapeutic drug-induced apoptosis appears to depend on the balance between proapoptotic and antiapoptotic signals. Therefore, it is possible that antiapoptotic signals such as the PI3K 1 -Akt survival cascade are involved in sensitivity to chemotherapeutic drugs. We reported that Akt inactivation sensitizes human ovarian cancer cells to cisplatin (1) and paclitaxel (2), suggesting that Akt inactivation could be a hallmark for examining the sensitivity of cells to some chemotherapeutic drugs. Possible mechanisms by which Akt promotes cell survival include phosphorylation and inactivation of the proapoptotic proteins BAD and caspase-9 (3, 4). Akt also phosphorylates and inactivates the Forkhead transcription factors, resulting in reduced expression of the cell cycle inhibitor p27 Kip1 and the Fas ligand (5-7). Via the phosphorylation of IB kinase, Akt also activates NFB, a transcription factor that has been implicated in cell survival (8,9).NFB is activated in certain cancers and in response to chemotherapy and radiation. NFB normally resides in the cytoplasm as an inactivated form in a complex with IB␣. Phosphorylation of IB␣ by upstream kinases promotes its degradation, allowing NFB to translocate to the nucleus and induce target genes (6, 7). The transcriptional activation of genes associa...

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

“…1B). At a concentration of 5 μmol/L, BAY 11-7082 had no significant inhibitory growth effects as indicated previously (5). Similarly, the DNA fragmentation assay showed that cell death induced by Taxol and parthenolide occurred via the activation of an apoptotic program (data not shown).…”

“…Although the molecular basis of resistance to Taxol is not well-documented, mounting evidence supports the role of intrinsically or constitutively activated nuclear factor-κB (NF-κB) in affording protection against programmed cell death. Constitutive high levels of NF-κB activity have been detected in response to chemotherapy and radiation in ovarian cancer (3)(4)(5), pancreatic cancer (6), breast cancer (7,8), and prostate cancer (9). Our recent work has revealed that nuclear RelA and cytoplasmic pI-κBα are significantly associated with a poor prognosis in cancer (10).…”

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

“…Ten days after transplantation, the control group received i.p. injections of DMSO whereas BAY11-7082-treated animals were injected with 5 g/g dose, three times per week for 3 weeks as described (49). Tumors were measured weekly, and volume was calculated as V (mm 3 ) ϭ A(mm) ϫ B 2 (mm 2 ) ϫ /6, B being the smaller dimension.…”

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

“…Cisplatin significantly inhibited cell viability in a dose-dependent manner in cisplatin-sensitive A2780 cells, but not in cisplatin-resistant A2780CP cells as reported previously. 25 After 72 h treatment, cell survival decreased from 100-68, 45 and 15% when cisplatin was administered at 1, 10 and 100 mM respectively in A2780 cells (Fig. 1A, black bars).…”