Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis.
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Lu Jun, Yang Ya-Qin, Tang Jia-Yi, Lou Si-Yue, Wang Chen, Hu Hong-Tao, Zheng Ya-Nan, An Hai, Ni Mao-Wei, Zhao Hua-Jun
Аннотация
BACKGROUND: The generation of drug-resistance limits chemotherapy application such as phosphoinositide 3-kinase δ (PI3Kδ) inhibitors in mantle cell lymphoma (MCL). Propolis has been regarded as a resistance reversal agent for many tumors, but its role in the sensitivity of MCL to PI3Kδ inhibitors remains unclear.
PURPOSE: The study investigated the synergistic effect, material basis and underlying mechanism of propolis in PI3Kδ inhibitor-resistant MCL cells.
METHODS: A PI3Kδ inhibitor resistance-acquired model was established and proteomics was utilized to identify differentially expressed proteins. The ethanol extract of propolis (EEP) was obtained and its components were detected by using UPLC-Q-TOF-MS/MS analysis. Active ingredients with potential resistance-reversal effect were obtained by reverse pharmacology. The sensitizing effect of caffeic acid phenethyl ester (CAPE) on idelalisib was demonstrated by cell viability assay in vitro and tumor-growth study in vivo. RNA-sequencing was applied to obtain CAPE-regulated genes. The occurrence of ferroptosis was confirmed by relevant detections such as lipid ROS detection. The regulation of chromobox homolog 5 (CBX5) was achieved by molecular inhibitors, transfection of recombinant plasmid or siRNA.
RESULTS: EEP combined with idelalisib synergistically reduced the viability of resistant MCL cells, with CAPE playing a major role. The combination of CAPE and idelalisib combated the growth of idelalisib-resistant MCL cells in vivo and in vitro by inducing ferroptosis. The CBX5 level influences the sensitivity to PI3Kδ inhibitors, and CAPE reversed resistance in MCL-R by inducing CBX5-mediated ferroptosis.
CONCLUSIONS: CBX5 loss drives Pl3Kδ inhibitor resistance in MCL and CAPE in propolis restores sensitivity by inducing CBX5-mediated ferroptosis. This is the first study to demonstrate the reversal of PI3Kδ inhibitor resistance through CAPE-induced ferroptosis via CBX5 modulation.
PURPOSE: The study investigated the synergistic effect, material basis and underlying mechanism of propolis in PI3Kδ inhibitor-resistant MCL cells.
METHODS: A PI3Kδ inhibitor resistance-acquired model was established and proteomics was utilized to identify differentially expressed proteins. The ethanol extract of propolis (EEP) was obtained and its components were detected by using UPLC-Q-TOF-MS/MS analysis. Active ingredients with potential resistance-reversal effect were obtained by reverse pharmacology. The sensitizing effect of caffeic acid phenethyl ester (CAPE) on idelalisib was demonstrated by cell viability assay in vitro and tumor-growth study in vivo. RNA-sequencing was applied to obtain CAPE-regulated genes. The occurrence of ferroptosis was confirmed by relevant detections such as lipid ROS detection. The regulation of chromobox homolog 5 (CBX5) was achieved by molecular inhibitors, transfection of recombinant plasmid or siRNA.
RESULTS: EEP combined with idelalisib synergistically reduced the viability of resistant MCL cells, with CAPE playing a major role. The combination of CAPE and idelalisib combated the growth of idelalisib-resistant MCL cells in vivo and in vitro by inducing ferroptosis. The CBX5 level influences the sensitivity to PI3Kδ inhibitors, and CAPE reversed resistance in MCL-R by inducing CBX5-mediated ferroptosis.
CONCLUSIONS: CBX5 loss drives Pl3Kδ inhibitor resistance in MCL and CAPE in propolis restores sensitivity by inducing CBX5-mediated ferroptosis. This is the first study to demonstrate the reversal of PI3Kδ inhibitor resistance through CAPE-induced ferroptosis via CBX5 modulation.