Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells
The anthracycline antibiotic doxorubicin (DOX) has been used successfully for treating various types of cancers. However, the therapeutic efficacy of DOX was greatly restricted by its cumulative dose-related cardiotoxicity and common side effects such as bone marrow and immune suppression. Quercetin had better cardioprotective and hepatoprotective activities. The present study was to observe whether quercetin could improve therapeutic index of DOX and explore its mechanisms.
Effects of quercetin on doxorubicin (DOX)-induced cytotoxicity were investigated in 4T1 cells and murine spleen cells by methylthiazoletetrazolium assay, flow cytometry and single cell gel electrophoresis. Influences of quercetin on therapeutic efficacy and systemic toxicity of DOX were evaluated in BALB/c mice with 4T1 breast cancer. Hypoxia-inducible factor-1 alpha (HIF-1α) in tumor and normal cells was examined to explore mechanisms of quercetin by Western blot and enzyme-linked immunosorbent assay.
In vitro, quercetin at dose less than 100 μM had only slight effects on cell viability and DOX-induced cytotoxicity in 4T1 cells under normoxia, but it could reverse 4T1 cell resistance to DOX under hypoxia and protect spleen cells against DOX-induced cytotoxicity. In vivo, quercetin suppressed tumor growth and prolonged survival in BALB/c mice bearing 4T1 breast cancer. Importantly, quercetin enhanced therapeutic efficacy of DOX and simultaneously reduced DOX-induced toxic side effects. Further study showed that quercetin suppressed intratumoral HIF-1α in a hypoxia-dependent way but increased its accumulation in normal cells. HIF-1α siRNA abolished effects of quercetin on both tumor and normal cells.
These results suggested that quercetin could improve therapeutic index of DOX by its opposing effects on HIF-1α in tumor and normal cells, and was a promising candidate as anticancer agents.
KeywordsQuercetin Doxorubicin Therapeutic index HIF-1α Breast cancer
- 22.Jeon H, Kim H, Choi D, Kim D, Park SY, Kim YJ, Kim YM, Jung Y (2007) Quercetin activates an angiogenic pathway, hypoxia inducible factor (HIF)-1-vascular endothelial growth factor, by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF prolyl hydroxylase. Mol Pharmacol 71:1676–1684CrossRefPubMedGoogle Scholar
- 23.Triantafyllou A, Liakos P, Tsakalof A, Chachami G, Paraskeva E, Molyvdas PA, Georgatsou E, Simos G, Bonanou S (2007) The flavonoid quercetin induces hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits cell proliferation by depleting intracellular iron. Free Radic Res 41:342–356CrossRefPubMedGoogle Scholar
- 26.Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC (2007) A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45:2179–2205CrossRefPubMedGoogle Scholar
- 28.Scambia G, Ranelletti FO, Panici PB, DeVincenzo R, Bonanno G, Ferrandina G, Piantelli M, Bussa S, Rumi C, Cianfriglia M, Mancuso S (1994) Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast cancer cell line: P-glycoprotein as a possible target. Cancer Chemother Pharmacol 34:459–464CrossRefPubMedGoogle Scholar