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Anticancer Drugs. 2019 Sep;30(8):838-845. doi: 10.1097/CAD.0000000000000781.

Ginsenoside Rd reverses cisplatin resistance in non-small-cell lung cancer A549 cells by downregulating the nuclear factor erythroid 2-related factor 2 pathway.

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The Criminal Science and Technology Department, Zhejiang Police College.
Institution of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, People's Republic of China.


Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the successful treatment of non-small-cell lung cancer (NSCLC). The nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway regulates the oxidative stress response, and in many cancer types, the high constitutive expression of NRF2 leads to proliferation and chemoresistance. Ginsenoside Rd (GS-Rd) is the main active component of ginsenosides. Here, GS-Rd was found to inhibit the proliferation of A549 lung cancer cells and induce G0/G1 phase arrest. We established cisplatin (DDP)-resistant A549 cell lines (A549/DDP). The half maximal inhibitory concentrations of DDP, gemcitabine, and adriamycin were much higher in A549/DDP cells than in A549 cells. The A549/DDP cell lines developed multidrug resistance, accompanied by activation of multidrug resistance protein 1 and multidrug resistance-associated protein 1, as well as NRF2 and its target genes. Treatment with GS-Rd inhibited the NRF2 pathway and significantly sensitized A549/DDP cells to therapeutic drugs. In addition, NRF2 knockdown attenuated the synergistic effects of GS-Rd in both A549 and A54/DDP cells. Taken together, these data show that NRF2 plays an important role in acquired drug resistance in NSCLC, and GS-Rd may ameliorate this chemoresistance by downregulating the NRF2 pathway. This study demonstrates that the NRF2 pathway may serve as a therapeutic target in NSCLC, and ginseng compounds may be effective for the treatment of this disease.

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