Combination of liquiritin, isoliquiritin and isoliquirigenin induce apoptotic cell death through upregulating p53 and p21 in the A549 non-small cell lung cancer cells

Liquiritin, isoliquiritin and isoliquirigenin are the active polyphenols present in Glycyrrhiza uralensis which has been used for the treatment of cancer and its complications. The present study was conducted to evaluate the cytotoxicity and antitumor activity of liquiritin, isoliquiritin and isoliquirigenin on human non-small lung cancer cells including apoptosis-induction, inhibition of apoptotic pathways and to explore the underlying mechanism. Lactate dehydrogenase assays, FITC Annexin V staining assay were performed to evaluate cellular cytotoxicity and apoptosis activity. The results showed that pretreatment with these polyphenols induced apoptosis in A549 cells. Liquiritin, isoliquiritin and isoliquirigenin significantly increased cytotoxicity of, and upregulated p53 and p21 and downregulated the apoptotic pathways. Furthermore, it inhibited cell cycle at the G2/M phase. Western blot analysis showed it significantly decreased the protein expression of PCNA, MDM2, p-GSK-3, p-Akt, p-c-Raf, p-PTEN, caspase-3, pro-caspase-8, pro-caspase-9 and PARP, Bcl-2 in a concentration-dependent manner while the protein expression of p53, p21 and Bax was increased. In addition, Akt pathway was downregulated. These findings suggest that liquiritin, isoliquiritin and isoliquirigenin inhibited the p53-dependent pathway and showed crosstalk between Akt activities. These active polyphenols can be an alternative agent for the treatment of lung cancer.