P-glycoprotein modulates oleanolic acid effects in hepatocytes cancer cells and zebrafish embryos
Maya Kayouka1, Aline Hamade2, Eliane Saliba3
1Bioactive Molecules Research Laboratory, Faculty of Sciences, Section II, Lebanese University, Lebanon.
Abstract:
Oleanolic acid (OA) is a triterpenoid, widely found in plants and possesses antitumor activity in many cancer lines. However, cancer cells develop multidrug resistance (mdr) hindering the effect of anticancer drugs. P-glycoprotein (P-gp) is a major cause of mdr. Therefore, the cytotoxic effect of OA was evaluated on human breast cancer MDA-MB-231 and human liver cancer HepG2 with absence and presence of P-gp, respectively. OA reduced MDA-MB-231 viability in a dose dependent manner, whereas no remarkable effect was observed on HepG2 in the same range of concentrations (1-60 μM). Moreover, cytotoxicity studies were conducted in the presence of verapamil (20 mg/L), a P-gp inhibitor. OA exhibited the same effect on MDA-MB-231 in the absence and presence of verapamil. However, the cytotoxicity was greatly enhanced for HepG2 cells in the presence of verapamil (cell viability dropped from 63.7% to 25% after 72 h at 60 μM). The results were then confirmed in vivo on zebrafish embryos. Increased mortality and malformations were observed in verapamil pretreated group between 5 and 15 μM of OA compared to control; also, all embryos died at 20 μΜ OA and above. These results demonstrate that inhibiting P-gp enhances the chemotherapeutic activity of OA.
Insights
Oleanolic acid shows antitumor potential, but multidrug resistance (mdr) limits its effectiveness. Inhibiting P-glycoprotein (P-gp) significantly enhances OA
Area of Science:
- Pharmacology
- Cancer Biology
- Natural Products Chemistry
Background:
- Oleanolic acid (OA), a plant-derived triterpenoid, exhibits antitumor properties.
- Multidrug resistance (mdr), often mediated by P-glycoprotein (P-gp), compromises the efficacy of anticancer agents.
- Understanding OA's interaction with P-gp is crucial for overcoming cancer drug resistance.
Purpose of the Study:
- To evaluate the cytotoxic effect of oleanolic acid (OA) on human breast cancer (MDA-MB-231) and liver cancer (HepG2) cells.
- To investigate the role of P-glycoprotein (P-gp) in mediating resistance to OA.
- To assess the potential of P-gp inhibition in enhancing OA's chemotherapeutic activity.
Main Methods:
- In vitro cytotoxicity assays were performed on MDA-MB-231 and HepG2 cell lines with and without verapamil (a P-gp inhibitor).
- Dose-dependent effects of OA on cell viability were measured.
- In vivo studies utilized zebrafish embryos to confirm findings on mortality and malformations.
Main Results:
- OA demonstrated dose-dependent cytotoxicity against MDA-MB-231 cells, irrespective of P-gp presence.
- HepG2 cells, which express P-gp, showed limited sensitivity to OA alone.
- Co-administration of verapamil significantly enhanced OA's cytotoxicity in HepG2 cells and increased mortality/malformations in zebrafish embryos.
Conclusions:
- P-glycoprotein (P-gp) contributes to resistance against oleanolic acid (OA) in certain cancer types.
- Inhibiting P-gp can restore or enhance the chemotherapeutic efficacy of OA.
- OA, in combination with P-gp inhibitors, represents a promising strategy for overcoming multidrug resistance in cancer therapy.
