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Lupiwighteone as an Antitumor Agent Reverses Multidrug Resistance in K562/ADR Cells by Regulating Cellular Prion
Kun Hu1, Jinling Zhang1, Yanan Zhang1
1School of Pharmacy, Changzhou University, 21 Gehu Road, Changzhou, Jiangsu, 213164, P.R. China.
Introduction:
One of the many reasons for cancer treatment failure and recurrence is acquired Multidrug Resistance (MDR). Overcoming cancer drug resistance has been the focus of researchers' studies. Cellular prion protein (PrPC) is a glycophosphatidylinositol-anchored cell-surface glycoprotein that has been implicated in tumor behavior, including proliferation, apoptosis, invasion, metastasis, and chemoresistance.
Methods:
Lupiwighteone (Lup), a natural isoflavone found in the root of Glycyrrhiza glabra, has anticancer activity against prostate cancer cells, neuroblastoma cells, and human breast cancer cells. However, its pharmacological effects and mechanisms in drug-resistant cancer cells have not been reported. In this study, we used an adriamycin- resistant leukemia K562 cell model, and for the first time, we investigated the reversal effect of Lup on its MDR and the potential mechanism.
Results:
The results indicated that Lup could induce apoptosis through the mitochondrial pathway while upregulating the expression of related apoptotic proteins, such as Bax, Cyto C, Caspase-3, and PARP1. Autophagy is commonly recognized as a protective mechanism that mediates MDR during treatment. We found that Lup induced cellular autophagy while upregulating the expression of related autophagy proteins such as Beclin 1 and LC3 II.
Conclusion:
In addition, when Lup was combined with adriamycin, Lup decreased the IC50 of K562/ADR cells; moreover, Lup can downregulate the expression of drug-resistant proteins, suggesting that Lup can reverse drug resistance. Further studies have shown that Lup can downregulate the expression of PrPC-PI3K-Akt axis proteins and PrPC-Oct4 axis proteins. This study demonstrated that Lup has the potential to inhibit the proliferation of K562/ADR cells by targeting PrPC, and further study of the signaling pathway associated with PrPC may provide the experimental basis for the treatment of drug-resistant leukemia.
Insights
Lupiwighteone (Lup) reverses adriamycin resistance in leukemia cells by inducing apoptosis and autophagy. This natural compound targets the PrPC-PI3K-Akt and PrPC-Oct4 pathways, offering potential for treating drug-resistant cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Acquired Multidrug Resistance (MDR) is a major cause of cancer treatment failure.
- Cellular prion protein (PrPC) is implicated in tumor progression and chemoresistance.
Purpose of the Study:
- To investigate the MDR reversal effects of Lupiwighteone (Lup) in adriamycin-resistant leukemia K562 cells.
- To elucidate the underlying mechanisms of Lup's action, focusing on PrPC signaling pathways.
Main Methods:
- Utilized an adriamycin-resistant leukemia K562 cell model.
- Assessed Lup's impact on apoptosis, autophagy, and the expression of key proteins.
- Investigated the modulation of PrPC-PI3K-Akt and PrPC-Oct4 signaling pathways.
Main Results:
- Lup induced apoptosis via the mitochondrial pathway, upregulating Bax, Cyto C, Caspase-3, and PARP1.
- Lup promoted autophagy by upregulating Beclin 1 and LC3 II.
- Lup decreased the IC50 of adriamycin-resistant cells and downregulated drug-resistant proteins.
Conclusions:
- Lupiwighteone demonstrates potential in reversing multidrug resistance in leukemia.
- Lup targets the PrPC-PI3K-Akt and PrPC-Oct4 axes, inhibiting proliferation of resistant cells.
- Further research into PrPC signaling pathways may offer new therapeutic strategies for drug-resistant leukemia.
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