Growth inhibitory and chemo-sensitization effects of naringenin, a natural flavanone purified from Thymus vulgaris, on human breast and colorectal cancer

Background: Natural products with diverse bioactivities are becoming an important source of novel agents with medicinal potential. Cancer is a devastating disease that causes the death of millions of people each year. Thus, intense research has been conducted on several natural products to develop novel anticancer drugs. Methods: Chromatographic and spectral techniques were used for the isolation and identification of naringenin (Nar). MTT, flow cytometry, western blotting, Real Time PCR were used to test anticancer and chemosensitizing effects of Nar, cell cycle, apoptosis, and expression of cell cycle, apoptosis, pro-survival and anti-survival-related genes. Results: In the present study, Thymus vulgaris ethanol extract was purified repeatedly to produce several compounds including the known flavanone, Nar which was identified using different spectral techniques. Nar was shown to inhibit both human colorectal and breast cancer cell growth in a dose- and time-dependent manner through cell cycle arrest at S- and G(2)/M-phases accompanied by an increase in apoptotic cell death. Additionally, Nar altered the expression of apoptosis and cell-cycle regulatory genes by down-regulating Cdk4, Cdk6, Cdk7, Bcl2, x-IAP and c-IAP-2 and up-regulating p18, p19, p21, caspases 3, 7, 8 and 9, Bak, AIF and Bax in both colorectal and breast cancer cells. Conversely, it diminished the expression levels of the cell survival factors PI3K, pAkt, pI kappa Ba and NF kappa Bp65. Moreover, Nar enhanced the sensitivity of colorectal and breast cancer cells to DNA-acting drugs. Discussion: These findings provide evidence that Nar's pro-apoptotic and chemo-sensitizing effects are mediated by perturbation of cell cycle, upregulation of pro-apoptotic genes and down-regulation of anti-apoptotic genes and inhibition of pro-survival signaling pathways. Conclusion: In conclusion, Nar might be a promising candidate for chemoprevention and/or chemotherapy of human cancers. However, further studies exploring this therapeutic strategy are necessary.