Tephrosin Suppresses the Chemoresistance of Paclitaxel-Resistant Ovarian Cancer via Inhibition of FGFR1 Signaling Pathway

Ovarian cancer is the leading cause of death among gynecologic cancers. Paclitaxel is used as a standard first-line therapeutic agent for ovarian cancer. However, chemotherapeutic resistance and high recurrence rates are major obstacles to treating ovarian cancer. We have found that tephrosin, a nat...

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Bibliographic Details
Published in:Biomedicines 2023-11, Vol.11 (12), p.3155
Main Authors: Kim, Hee Su, Bae, Sowon, Lim, Ye Jin, So, Kyeong A, Kim, Tae Jin, Bae, Seunghee, Lee, Jae Ho
Format: Article
Language:English
Subjects:
Acetylcysteine
AKT protein
Analysis
Apoptosis
Breast cancer
Cancer
Cell cycle
Cell viability
Chemoresistance
Chemotherapy
Cytotoxicity
Ethylenediaminetetraacetic acid
FGFR1/FRS2 signaling pathway
Fibroblast growth factor receptor 1
Flow cytometry
Fluo-3
Genes
Growth factors
Gynecology
Health aspects
Immunoblotting
Kinases
Lung cancer
MAP kinase
Ovarian cancer
P-Glycoprotein
Paclitaxel
paclitaxel resistance
Phosphorylation
Polymerase chain reaction
Prevention
Reactive oxygen species
Signal transduction
Stat3 protein
tephrosin
XIAP protein
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Summary:Ovarian cancer is the leading cause of death among gynecologic cancers. Paclitaxel is used as a standard first-line therapeutic agent for ovarian cancer. However, chemotherapeutic resistance and high recurrence rates are major obstacles to treating ovarian cancer. We have found that tephrosin, a natural rotenoid isoflavonoid, can resensitize paclitaxel-resistant ovarian cancer cells to paclitaxel. Cell viability, immunoblotting, and a flow cytometric analysis showed that a combination treatment made up of paclitaxel and tephrosin induced apoptotic death. Tephrosin inhibited the phosphorylation of AKT, STAT3, ERK, and p38 MAPK, all of which simultaneously play important roles in survival signaling pathways. Notably, tephrosin downregulated the phosphorylation of FGFR1 and its specific adapter protein FRS2, but it had no effect on the phosphorylation of the EGFR. Immunoblotting and a fluo-3 acetoxymethyl assay showed that tephrosin did not affect the expression or function of P-glycoprotein. Additionally, treatment with N-acetylcysteine did not restore cell cytotoxicity caused by a treatment combination made up of paclitaxel and tephrosin, showing that tephrosin did not affect the reactive oxygen species scavenging pathway. Interestingly, tephrosin reduced the expression of the anti-apoptotic factor XIAP. This study demonstrates that tephrosin is a potent antitumor agent that can be used in the treatment of paclitaxel-resistant ovarian cancer via the inhibition of the FGFR1 signaling pathway.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11123155