Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3

• Luteolin inhibits cell growth in breast cancer MDA-MB-231 cells.
• Combination treatment with luteolin and paclitaxel enhanced apoptosis in MDA-MB-231 cells.
• Combination treatment increased Fas expression and activated caspase-8 and -3.
• The STAT3 signaling pathway was involved in the enhancement of apoptosis.
• Combination treatment promoted the reduction effect on tumor growth in nude mice.

The potential use of low-dose chemotherapy has been appealing because lower dosages are more attainable during cancer therapy and cause less toxicity in patients. Combination therapy of paclitaxel, a promising frontline chemotherapy agent, with natural anti-tumor agents that are considerably less toxic and possess the capability of activating additional apoptotic signals may provide a rational molecular basis for novel chemotherapeutic strategies. Luteolin, a natural flavone, possesses multiple biological activities, including anti-tumor potential. In the present study, the effects of concomitant administration of luteolin and paclitaxel were investigated in human breast cancer MDA-MB-231 cells. Luteolin alone demonstrated an anti-proliferative effect. Co-administration of luteolin and paclitaxel resulted in an increase in apoptosis compared with the treatment of paclitaxel alone as evidenced by the results of a diamidino-2-phenylindole (DAPI) stain and Annexin-V-based assay. Moreover, immunoblotting analysis also showed that the co-administration of luteolin and paclitaxel activated caspase-8 and caspase-3 and increased the expression of Fas. Furthermore, the increased expression of Fas due to co-administration was shown to be due to the blocking of signal transducer and activator of transcription 3 (STAT3). Finally, combination therapy with luteolin and paclitaxel significantly reduced tumor size and tumor weight in an orthotopic tumor model of MDA-MB-231 cells in nude mice. These results suggest that the luteolin–paclitaxel combination could be a novel strategy for the treatment of breast cancer.