Inhibition of Kpn$β$1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer. Chi, R., van der Watt, P., Wei, W., Birrer, M., & Leaner, V. BMC Cancer, 2021.
doi  abstract   bibtex   
Background: Inhibition of nuclear import via Karyopherin beta 1 (Kpn$β$1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. Methods: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NF$κ$B was determined after co-treatment of cells. Results: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpn$β$1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NF$κ$B, which was diminished upon pre-treatment with INI-43. NF$κ$B reporter activity and expression of NF$κ$B transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. Conclusions: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NF$κ$B. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.
@article{Chi2021a,
abstract = {Background: Inhibition of nuclear import via Karyopherin beta 1 (Kpn$\beta$1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. Methods: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NF$\kappa$B was determined after co-treatment of cells. Results: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpn$\beta$1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NF$\kappa$B, which was diminished upon pre-treatment with INI-43. NF$\kappa$B reporter activity and expression of NF$\kappa$B transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. Conclusions: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NF$\kappa$B. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.},
author = {Chi, R.-P.A. and van der Watt, P. and Wei, W. and Birrer, M.J. and Leaner, V.D.},
doi = {10.1186/s12885-021-07819-3},
journal = {BMC Cancer},
number = {1},
title = {{Inhibition of Kpn$\beta$1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer}},
volume = {21},
year = {2021}
}

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