Antitumor activity of a novel STAT3 inhibitor and redox modulator in non-small cell lung cancer cells

Xiaoying Liu, Wei Guo, Shuhong Wu, Li Wang, Ji Wang, Bingbing Dai, Edward S. Kim, John V. Heymach, Michael Wang, Luc Girard, John Minna, Jack A. Roth, Stephen G. Swisher, Bingliang Fang

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28 Scopus citations

Abstract

NSC-743380 is a novel STAT3 inhibitor that suppresses the growth of several NCI-60 cancer cell lines derived from different tissues and induces regression of xenograft tumors in vivo at various doses. To evaluate the antitumor activity of NSC-743380 in lung cancer cells, we analyzed the susceptibility of 50 NSCLC cell lines to this compound using cell viability assay. About 32% (16 of 50) of these cell lines were highly susceptible to this compound, with a 50% inhibitory concentration (IC 50) of <1 μM. In mechanistic studies, the increased numbers of apoptotic cells as well as increased PARP cleavage showed that cytotoxic effects correlate with apoptosis induction. Treatment with NSC-743380 inhibited transcription factor STAT3 activation and induced ROS production in sensitive human lung cancer cell lines but not in resistant cells. Blocking ROS generation with the antioxidant NDGA dramatically abolished NSC-743380-induced growth suppression and apoptosis, but had minimal effect on NSC-743380-induced STAT3 inhibition, suggesting that STAT3 inhibition is not caused by ROS production. Interestingly, knockdown of STAT3 with use of shSTAT3 induced ROS generation and suppressed tumor cell growth. Moreover, scavenging ROS induced by STAT3 inhibition also diminished antitumor activity of STAT3 inhibition. In vivo administration of NSC-743380 suppressed tumor growth and p-STAT3 in lung tumors. Our results indicate that NSC-743380 is a potent anticancer agent for lung cancer and that its apoptotic effects in lung cancer cells are mediated by induction of ROS through STAT3 inhibition.

Original languageEnglish (US)
Pages (from-to)1456-1464
Number of pages9
JournalBiochemical Pharmacology
Volume83
Issue number10
DOIs
StatePublished - May 15 2012

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Keywords

  • Drug development
  • Lung Cancer
  • Reactive oxygen species
  • STAT3

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Liu, X., Guo, W., Wu, S., Wang, L., Wang, J., Dai, B., Kim, E. S., Heymach, J. V., Wang, M., Girard, L., Minna, J., Roth, J. A., Swisher, S. G., & Fang, B. (2012). Antitumor activity of a novel STAT3 inhibitor and redox modulator in non-small cell lung cancer cells. Biochemical Pharmacology, 83(10), 1456-1464. https://doi.org/10.1016/j.bcp.2012.02.010