KPT‐330 and Y219 exert a synergistic antitumor effect in triple‐negative breast cancer through inhibiting NF‐κB signaling

Abstract

Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype, which has poor prognosis due to the lack of effective targeted drugs. KPT‐330, an inhibitor of the nuclear export protein CRM‐1, has been widely used in clinical medicine. Y219, a novel proteasome inhibitor designed by our group, shows superior efficacy, reduced toxicity, and reduced off‐target effects as compared to the proteasome inhibitor bortezomib. In this study, we investigated the synergistic effect of KPT‐330 and Y219 against TNBC cells, as well as the underlying mechanisms. We report that combination treatment with KPT‐330 and Y219 synergistically inhibited the viability of TNBC cells in vitro and in vivo. Further analysis revealed that the combined use of KPT‐330 and Y219 induced G2‐M phase arrest and apoptosis in TNBC cells, and attenuated nuclear factor kappa B (NF‐κB) signaling by facilitating nuclear localization of IκB‐α. Collectively, these results suggest that the combined use of KPT‐330 and Y219 may be an effective therapeutic strategy for the treatment of TNBC.

The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

“…In vitro 178,313 Bcl-xL/Bcl-2 inhibitor in vitro and vivo 320 ; Irradiation in vitro and in vivo 186 ; olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in vitro and vivo 321 Lung cancer Both Enzalutamide in vivo 322 ; cisplatin in vitro and vivo 190,322 ; irinotecan in vitro and vivo 190 ; KRAS G12C inhibitor in vitro and vivo 191 ; PARP1 inhibition in vitro and vivo 189 ; Bcl-xL inhibitor in vitro and vivo 184 Breast cancer Both 95,312 Tamoxifen in vitro and vivo 134 ; olaparib, a PARP inhibitor in vitro and vivo 199 ; LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling in vitro and in vivo 323 ; a PI3K/mTOR inhibitor in vitro and in vivo 197 ; tucidinostat in vitro and vivo 201 ; Y219, a novel proteasome inhibitor in vitro and vivo 324 (Continues)…”