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Mitochondrial targeting drug lonidamine triggered apoptosis in doxorubicin-resistant HepG2 cells
1Department of Biochemistry, The Chinese University of Hong Kong, Shatin, People's Republic of China.
Abstract:
Mitochondria play a crucial role in the induction and execution of apoptosis. Accordingly, recent suggestions have been made to use agents that directly act on mitochondria to trigger apoptosis so that drug-sensitive and-resistant tumour cells can be eliminated. To test this hypothesis, human hepatocarcinoma HepG2 and its derivative R-HepG2 with doxorubicin (Dox) resistance as a result of expression of P-glycoprotein were used to investigate the effect of lonidamine (LND), a new mitochondrial targeting drug, on the induction of apoptosis. Results from our study indicate that R-HepG2 cells were more sensitive to LND than parental cells in terms of cytotoxicity determined by alamar blue assay. Cell death induced by LND was associated with the hallmarks of apoptosis such as mitochondrial membrane depolarization, release of cytochrome c, phosphatidyl-serine externalization and DNA fragmentation. Moreover, combined treatment of cells with Dox and LND elicited more cell death. Taken together, our results suggest a potential use of LND as an anti-cancer drug to bypass drug resistance and to trigger tumour destruction through apoptosis in HepG2 and R-HepG2 cells.
Insights
Lonidamine (LND) effectively triggers apoptosis in drug-resistant liver cancer cells. This mitochondrial targeting drug shows promise in overcoming doxorubicin resistance and destroying tumors.
Area of Science:
- Cell Biology
- Pharmacology
- Oncology
Background:
- Mitochondria are key regulators of apoptosis, the programmed cell death pathway.
- Targeting mitochondria offers a strategy to eliminate both drug-sensitive and drug-resistant tumor cells.
- Doxorubicin (Dox) resistance in hepatocarcinoma cells, often mediated by P-glycoprotein, presents a significant clinical challenge.
Purpose of the Study:
- To investigate the efficacy of lonidamine (LND), a novel mitochondrial targeting agent, in inducing apoptosis in human hepatocarcinoma cells.
- To evaluate LND's effectiveness against doxorubicin (Dox)-resistant hepatocarcinoma cells (R-HepG2) compared to parental cells (HepG2).
- To explore the potential of LND as a therapeutic agent to overcome drug resistance and induce tumor cell death.
Main Methods:
- Utilized human hepatocarcinoma HepG2 and its Dox-resistant derivative R-HepG2 cell lines.
- Assessed cytotoxicity using the alamar blue assay.
- Investigated apoptosis induction through analysis of mitochondrial membrane potential, cytochrome c release, phosphatidylserine externalization, and DNA fragmentation.
Main Results:
- R-HepG2 cells exhibited greater sensitivity to LND-induced cytotoxicity than parental HepG2 cells.
- LND treatment induced characteristic apoptotic events, including mitochondrial depolarization, cytochrome c release, and DNA fragmentation.
- Combined treatment with Dox and LND resulted in enhanced cancer cell death.
Conclusions:
- Lonidamine demonstrates significant potential as an anti-cancer drug by effectively inducing apoptosis.
- LND can overcome doxorubicin resistance in hepatocarcinoma cells.
- This study suggests LND's utility in triggering tumor destruction through apoptosis, offering a new therapeutic avenue for resistant cancers.