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Anti-tumor compound RY10-4 suppresses multidrug resistance in MCF-7/ADR cells by inhibiting PI3K/Akt/NF-κB signaling
Xiaofan Yang1, Yufeng Ding2, Miao Xiao2
1Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract:
RY10-4, an anti-tumor agent, exerts cytotoxicity to various human cancer cell lines. However, few studies reported the effect of combined application of RY10-4 and chemotherapeutic drugs against cancer cells with multidrug resistance (MDR). In this study, P-glycoprotein (P-gp), which is reported to mediate MDR to anti-cancer drugs, was proved to be overexpressed in the adriamycin (ADR)-resistant human breast cancer cells, namely MCF-7/ADR cells. Furthermore, RY10-4 application resulted in a downregulation of P-gp in MCF-7/ADR cells, thus leading to higher chemosensitivity to ADR. Our study further demonstrated that the MDR phenomenon was under the control of the PI3K/Akt/NF-κB pathway, which was suppressed by RY10-4, leading to MDR reversal effects in MCF-7/ADR cells. In vivo, MCF-7/ADR cells were effectively suppressed by the combined ADR/RY10-4 treatment compared with the ADR-alone treatment. Taken together, these results demonstrated that RY10-4 reverses the MDR phenotype in MCF-7/ADR cells by suppressing the PI3K/Akt/NF-κB pathway.
Insights
RY10-4 combats multidrug resistance (MDR) in breast cancer by downregulating P-glycoprotein (P-gp) and inhibiting the PI3K/Akt/NF-κB pathway. This combined therapy enhances sensitivity to adriamycin (ADR), showing significant in vivo tumor suppression.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in cancer limits chemotherapy efficacy.
- P-glycoprotein (P-gp) overexpression is a key mechanism mediating MDR.
- The PI3K/Akt/NF-κB pathway is implicated in MDR development.
Purpose of the Study:
- To investigate the effect of RY10-4 on adriamycin (ADR)-resistant breast cancer cells (MCF-7/ADR).
- To determine if RY10-4 can reverse MDR by targeting P-gp and the PI3K/Akt/NF-κB pathway.
- To evaluate the in vivo efficacy of combined ADR and RY10-4 treatment.
Main Methods:
- MCF-7/ADR cells were used to model adriamycin resistance.
- P-gp expression levels were analyzed in response to RY10-4 treatment.
- The PI3K/Akt/NF-κB signaling pathway was assessed.
- In vitro and in vivo experiments evaluated the combined effect of ADR and RY10-4.
Main Results:
- RY10-4 downregulated P-gp expression in MCF-7/ADR cells.
- RY10-4 treatment increased chemosensitivity to ADR.
- RY10-4 suppressed the PI3K/Akt/NF-κB pathway in resistant cells.
- Combined ADR/RY10-4 treatment showed superior tumor suppression in vivo compared to ADR alone.
Conclusions:
- RY10-4 effectively reverses the MDR phenotype in MCF-7/ADR cells.
- Inhibition of the PI3K/Akt/NF-κB pathway by RY10-4 is crucial for MDR reversal.
- Combined ADR and RY10-4 therapy presents a promising strategy for overcoming MDR in breast cancer.
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