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Solasodine targets NF-κB signaling to overcome P-glycoprotein mediated multidrug resistance in cancer.
- Source :
-
Experimental Cell Research . Aug2024, Vol. 441 Issue 1, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
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Abstract
- P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is the leading cause of chemotherapy failure since it causes the efflux of chemotherapeutic drugs from the cancer cells. Solasodine, a steroidal alkaloid and oxaspiro compound, present in the Solanaceae family showed significant cytotoxic effects on various cancer cells. However, the effect of solasodine on reversing P-gp mediated drug resistance is still unknown. Primarily in this study, the integrative network pharmacology analysis found 71 common targets between solasodine and cancer MDR, among them NF-κB was found as a potential target. The results of immunofluorescence analysis showed that solasodine significantly inhibits NF-κB-p65 nuclear translocation which caused downregulated P-gp expression in KBChR-8-5 cells. Further, solasodine binds to the active sites of the TMD region of P-gp and inhibits P-gp transport activity. Moreover, solasodine significantly promotes doxorubicin intracellular accumulation in the drug resistant cells. Solasodine reduced the fold resistance and synergistically sensitized doxorubicin's therapeutic effects in KBChR-8-5 cells. Additionally, the solasodine and doxorubicin combination treatment increased the apoptotic cell populations and G2/M phase cell cycle arrest in KBChR-8-5 cells. The MDR tumor bearing xenograft mice showed tumor-suppressing characteristics and P-gp downregulation during the combination treatment of solasodine and doxorubicin. These results indicate that solasodine targets NF-κB signaling to downregulate P-gp overexpression, inhibit P-gp transport activity, and enhance chemosensitization in MDR cancer cells. Considering its multifaceted impact, solasodine represents a potent natural fourth-generation P-gp modulator for reversing MDR in cancer. [Display omitted] • Solasodine effectively reversed P-glycoprotein (P-gp) mediated multidrug resistance in KBChR-8-5 cancer cells. • Solasodine inhibits NF-κB signaling pathway which downregulates P-gp overexpression in KBChR-8-5 cells. • Solasodine actively binds to the P-gp drug binding pocket and inhibits its drug efflux activity. • In combination with doxorubicin, solasodine synergistically enhanced the chemosensitivity of doxorubicin in KBChR-8-5 cells. • Moreover, solasodine and doxorubicin combination suppressed the tumor growth in MDR tumor bearing nude mice. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00144827
- Volume :
- 441
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Experimental Cell Research
- Publication Type :
- Academic Journal
- Accession number :
- 178641883
- Full Text :
- https://doi.org/10.1016/j.yexcr.2024.114153