Nifuroxazide boosts the anticancer efficacy of palbociclib-induced senescence by dual inhibition of STAT3 and CDK2 in triple-negative breast cancer

Abstract

Though palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor has been approved for treating breast cancer, two major clinical challenges remain: (i) Triple-negative breast cancer (TNBC) appears to be more resistant to palbociclib, and (ii) Palbociclib-induced senescence-associated secretory phenotype (SASP) has a pro-tumorigenic function. Here we report that combining palbociclib with the STAT3 inhibitor nifuroxazide uncouples SASP production from senescence-associated cell cycle exit. Moreover, we identified nifuroxazide as a CDK2 inhibitor that synergistically promotes palbociclib-induced growth arrest and senescence in TNBC cells. In vitro, the combination of nifuroxazide with palbociclib further inhibited the TNBC cell proliferation and enhanced palbociclib-induced cell cycle arrest and senescence. The modulation of palbociclib-induced SASP by nifuroxazide was associated with the reduction of phosphorylated-STAT3. Nifuroxazide also blocks SASP-dependent cancer cell migration. Furthermore, thermal shift assay and molecular docking of nifuroxazide with STAT3 and CDK2 revealed that it binds to their active sites and acts as a potent dual inhibitor. In vivo, the combination of nifuroxazide with palbociclib suppressed 4T1 tumor growth and lung metastasis. Our data suggest that nifuroxazide enhances the anticancer effects of palbociclib in TNBC by uncoupling SASP production from senescence-associated cell cycle exit and inhibiting CDK2 to promote tumor senescence.

Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer

“…Research has identified a wide array of small molecules that exhibit the potential to inhibit TNBC cell viability. This includes Dihydrotanshinone ( 166 ), DT-13 ( 167 ), Cucurbitacin E ( 168 – 170 ), Niclosamide ( 171 – 173 ), SG-1709 ( 174 ), SG-1721 ( 174 ), Nifuroxazide ( 175 , 176 ), LLY17 ( 177 ), 6Br-6a ( 178 ), Pyrimethamine ( 179 , 180 ), Pectolinarigenin ( 181 ), Flubendazole ( 182 , 183 ), Eupalinolide J ( 184 , 185 ), Betulinic acid ( 186 ), Carfilzomib ( 187 ), WP1066 ( 188 ), Rhus coriaria extract ( 189 ), FZU-03,010 ( 190 ), Disulfiram ( 191 ), Schisandrin B ( 192 ), Osthole ( 193 ), Brevilin A ( 194 ), Arnicolide D ( 195 ), Eucannabinolide ( 196 ), Pulvomycin ( 197 ), R001 ( 198 ), Salinomycin ( 199 , 200 ), the ethanolic extract of origanum syriacum ( 201 ), Apigenin ( 202 ), and AG-014699 ( 203 ). This inhibition is attributed to their ability to suppress STAT3 phosphorylation.…”

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

“…Dysregulation of these kinases, leading to uncontrolled cell proliferation, is a hallmark of cancer [ 73 ]. CDK2 [ 74 , 75 , 76 , 77 , 78 , 79 ] occupies a pivotal position in this regulatory network. Its influence extends beyond cell cycle transitions and G1/S and G2 phase progression to encompass DNA repair [ 80 ], gene transcription, and epigenetic modifications in tumors [ 81 , 82 , 83 ].…”