MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel

• Published in: Chinese science bulletin 2012-03, Vol.57 (9), p.1007-1012
• Main Authors: Shen, HongChang, Dong, Wei, Gao, DongWei, Wang, GuangHui, Ma, GuoYuan, Liu, Qi, Du, JiaJun
• Format: Article
• Language: English
• Subjects: A549细胞; antagonists; Apoptosis; Chemistry/Food Science; chemotherapy; cytotoxicity; Earth Sciences; Engineering; Humanities and Social Sciences; interphase; Life Sciences; lung neoplasms; MDM2; multidisciplinary; p53蛋白; paclitaxel; Physics; radiotherapy; Science; Science (multidisciplinary); 保护; 拮抗剂; 癌细胞; 紫杉醇; 野生型
• ISSN: 1001-6538; 1861-9541
• DOI: 10.1007/s11434-012-4984-7

The p53 pathway has an important role in cell cycle arrest and apoptosis. Downregulated levels of p53 have been shown to increase resistance to the cytotoxic effects of chemotherapy or radiotherapy. MDM2 (murine double minute 2) is able to bind p53 and modulate its transcriptional activity and stability. We studied the effect of Nutlin-3a, an MDM2 antagonist, on the response of non-small cell lung cancer cell lines, A549 (p53+/+) and H1299 (p53−/−), to paclitaxel (Taxol). A549 cells treated with Nutlin-3a plus paclitaxel showed a significant increase in MDM2 and wild-type p53 protein, a marked increase in the number of cells in the G0–G1 and G2-M phases, and a significant decrease in the percentage of cells in the S phase. The percentage of apoptotic A549 cells treated with 10 μmol/L Nutlin-3a plus 10 nmol/L paclitaxel was significantly lower than those treated with paclitaxel alone, and was also lower than that observed in H1299 cells. MTT assays demonstrated that Nutlin-3a plus paclitaxel also significantly reduced the sensitivity of A549 cells to paclitaxel compared with that of H1299 cells. In conclusion, Nutlin-3a mediates the cytotoxic effect of paclitaxel depending on p53 status. It may also protect wild-type p53 cells from mitotic chemotherapeutics.