Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

Abstract

The transcription factor NF-kB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that di er in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 mM) and doxorubicin (0.3 mM): Highly sensitive BxPC-3 and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kB activity in all cell lines, whereas basal NF-kB binding was nearly undetectable in BxPc-3 and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkBa super-repressor, strongly enhanced the apoptotic e ects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kB activity rather than the transient induction of NF-kB by some anti-cancer drugs. Blockade of basal NF-kB activity by well established drugs e ciently reduces chemoresistance of pancreatic cancer cells and o ers the potential for improved therapeutic strategies. Oncogene (2001) 20, 859 ± 868.

NF‐kB inhibition as a strategy to enhance etoposide‐induced apoptosis in K562 cell line

“…In line with these data, we have shown that NF-kB inhibition may be a strategy to increase sensitivity to Etoposide-induced apoptosis in a cell line derived from a CML blast crisis. We have first shown that Etoposide, which is extensively used in the therapy of myeloid leukemias, activates NF-kB in K562 cell line, as it has been described in pancreatic cancer cell lines [21][22][23]. Interestingly, the kinetic of activation is sensibly different to that observed with the traditional NF-kB activator, TNF-a.…”

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

“…The observation that patients overexpressing RelA show a dramatically decreased survival time may allow stratifying patients into two subgroups: one subgroup is likely to benefit from NF-kB-inhibiting agents and another subgroup which has a relatively good survival perspective irrespective of such a treatment, potentially because resistance to conventional chemotherapeutics due to NF-kB activation has not occurred yet (Arlt et al, 2001(Arlt et al, , 2003. This possibility should be considered when clinical trials with NF-kB-inhibiting agents are being planned.…”

“…In another study, NF-kB was found to be activated in a number of pancreatic cancer cell lines, which was later linked to chemotherapy resistance (Arlt et al, 2001(Arlt et al, , 2003. Consequently, inhibition of NF-kB activation in these cell lines using sulfasalazine or the proteasome inhibitor MG-132 resulted in their sensitisation to etoposide, doxorubicin (Arlt et al, 2001) and gemcitabine (Arlt et al, 2003). More recently, overexpression of several NF-kB subunits was described in the cytoplasm as well as in the nucleus of the pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3 (Chandler et al, 2004).…”

“…Furthermore, they profiled a small set of pancreatic tumours immunohistochemically and detected nuclear RelA. In another study, NF-kB was found to be activated in a number of pancreatic cancer cell lines, which was later linked to chemotherapy resistance (Arlt et al, 2001(Arlt et al, , 2003. Consequently, inhibition of NF-kB activation in these cell lines using sulfasalazine or the proteasome inhibitor MG-132 resulted in their sensitisation to etoposide, doxorubicin (Arlt et al, 2001) and gemcitabine (Arlt et al, 2003).…”

Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

“…Most chemotherapy and radiation treatments induce apoptosis (programmed cell death) in tumor cells, 1,2 and apoptosis also seems to be the main mechanism behind the cell kill induced by a number of cytokines, such as tumor necrosis factor-␣ (TNF-␣). 3,4 However, TNF-␣, chemotherapy, radiation as well as other stimuli activate the transcriptional nuclear factor-B (NF-B), which suppresses the apoptotic potential of these stimuli in vitro.…”