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Published on: October 30, 2013
Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder
Yujiro Ito1, Eiji Kikuchi2, Nobuyuki Tanaka3
1Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. yujiroitouro@gmail.com.
Background:
No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells.
Methods:
Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro.
Results:
Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively.
Conclusion:
There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.
Insights
NF-κB blockade with DHMEQ effectively reduced cell viability and induced apoptosis in CDDP-resistant bladder cancer cells. Combining DHMEQ with paclitaxel significantly enhanced therapeutic effects in preclinical models, targeting NF-κB activation in resistant bladder tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Acquired resistance to cisplatin (CDDP) is a significant challenge in bladder cancer treatment.
- The role of NF-κB activation in CDDP-resistant bladder cancer remains largely unaddressed.
- This study investigates NF-κB blockade using DHMEQ in CDDP-resistant bladder cancer cells.
Purpose of the Study:
- To investigate NF-κB activation in CDDP-resistant bladder cancer cells.
- To evaluate the therapeutic efficacy of NF-κB blockade with DHMEQ in CDDP-resistant bladder cancer.
- To assess the combined effect of DHMEQ and paclitaxel in a preclinical model of acquired platinum-resistance.
Main Methods:
- Established a CDDP-resistant bladder cancer cell line (T24PR) from T24 cells.
- Assessed NF-κB activation (p65 expression and DNA-binding activity) via Western blotting and EMSA.
- Evaluated cytotoxic effects and apoptosis induction in vitro and in vivo using DHMEQ and paclitaxel.
Main Results:
- T24PR cells exhibited significantly enhanced intranuclear p65 expression and NF-κB DNA-binding activity compared to T24 cells.
- DHMEQ treatment alone reduced cell viability and induced apoptosis in T24PR cells.
- Combination therapy with DHMEQ and paclitaxel demonstrated a significant reduction in tumor volume in mouse xenografts compared to paclitaxel alone (66.9% vs. 17.0% reduction).
Conclusions:
- Elevated NF-κB nuclear localization is a distinct feature of acquired platinum-resistance in bladder cancer.
- NF-κB blockade with DHMEQ shows promise as a therapeutic strategy for CDDP-resistant bladder cancer.
- Combination therapy targeting NF-κB may overcome chemoresistance and improve treatment outcomes in bladder cancer.
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