Cryptotanshinone Reverses Cisplatin Resistance of Human Lung Carcinoma A549 Cells through Down-Regulating Nrf2 Pathway.
Xia C1, Bai X, Hou X, Gou X, Wang Y, Zeng H, Huang M, Jin J.
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1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Abstract
BACKGROUND/AIMS:
To explore whether Nrf2 was associated with drug-resistance in cisplatin resistant A549 (A549/DDP) cells, and if cryptotanshinone (CTS), one of the bioactive compounds isolated from the roots of Salvia miltiorrhiza Bunge (Danshen), could enhance the sensitivity in A549/DDP cells towards cisplatin.
METHODS:
A549 and A549/DDP cells were subjected to various treatments, and then Sulforhodamine B (SRB) assay, flow cytometry analysis and western immunoblotting analysis were applied to determine IC50, apoptotic status and expressions of Nrf2 and its downstream genes.
RESULTS:
The endogenous expression levels of Nrf2 as well as its target genes including GCLC, GCLM, HO-1, NQO1 and MRP1 were much higher in A549/DDP cells than those of A549 cells and the susceptibility of A549/DDP cells to cisplatin was partially restored by silencing Nrf2. The combination of CTS and cisplatin led to cell death and apoptosis through sensitizing A549/DDP cells towards cisplatin compared with cisplatin mono-treatment, however, this reversal role could be abolished by Nrf2 knockdown. Specifically, CTS obviously diminished Nrf2 expression, thus contributing to the decrease of Nrf2-target genes expression levels. Meanwhile, we also discovered that CTS triggered several other signals involving in chemoresistance such as MAPKs, Akt and STAT3 pathway.
CONCLUSION:
Our data indicated CTS may be developed as a potential sensitizer cooperating with anticancer drugs to combat chemoresistant carcinoma through the inhibition of the Nrf2 pathway.