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Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC

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Abstract

This study was aimed to elucidate the roles of inhibition of related JAK/STAT pathways in regulating cytotoxicity induced by cisplatin in non-small-cell lung cancer (NSCLC) cell. We treated five non-small-cell lung cancer cell lines with cisplatin alone or with cisplatin and Jak2 inhibitor (ruxolitinib) and assessed cell viability, expression of Jak2 and STAT3 and cell apoptosis. We also investigated the effect of combination treatment inhibited tumor xenograft growth in two human NSCLC xenograft models bearing the cisplatin resistant (H1299) and sensitive (A549) cells. Different cell lines with different genetic background showed half-maximal inhibitory concentrations (IC50) of cisplatin from 4.66 to 68.28 µmol/L. They could be divided into cisplatin intrinsic resistant and cisplatin sensitive cell lines. In cisplatin-resistant cells with higher Jak2 and STAT3 expression, cisplatin and ruxolitinib combination dramatically suppressed the cell growth, down-regulated the expression of phosphorylated STAT3 and induced cleaved caspase-3 expression. Moreover combination with cisplatin and ruxolitinib also significantly inhibited the growth of resistant cell H1299, A549/DDP and H2347 in soft agar model. Finally, combination group significant inhibited the tumor growth and induced the caspase-3 expression compared with either single agent alone (P < 0.05) on the resistant cell xenografts model. The present study indicates that further study is warranted to determine the effectiveness of combination treatment with cisplatin and Jak2/stat3 pathway inhibitor for platinum-resistant NSCLC.

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Acknowledgments

This work was supported, in whole or in part, by National Nature and Science Foundation of China (No 81173579). And also we are grateful thank for PhD. Aislyn D. W. Boran to help us improve our English.

Conflict of interest

We have no competing interests and conflict interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital, No.28 FuXing Road, Beijing, 100853, China

    Yuan Hu, Ping Liu & Dai-Hong Guo

  2. Pharmacy Care Center, Chinese PLA General Hospital, Beijing, 100853, China

    Yin Hong & YuanJie Xu

  3. Department of Pharmacology and System Therapeutics, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Yibang Chen

Authors
  1. Yuan Hu
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  2. Yin Hong
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  3. YuanJie Xu
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  4. Ping Liu
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  5. Dai-Hong Guo
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  6. Yibang Chen
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Corresponding author

Correspondence to Ping Liu.

Additional information

Yuan Hu and Yin Hong have contributed equally to this work.

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Hu, Y., Hong, Y., Xu, Y. et al. Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis 19, 1627–1636 (2014). https://doi.org/10.1007/s10495-014-1030-z

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