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Investigational New Drugs

, Volume 37, Issue 5, pp 828–836 | Cite as

The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling

  • Juan Wang
  • Shumei Ma
  • Xiuhua Chen
  • Sanqi Zhang
  • Zhiyong WangEmail author
  • Qibing MeiEmail author
PRECLINICAL STUDIES

Summary

Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti-tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic.

Keywords

Lung cancer Sorafenib S1 Angiogenesis Phosphorylation 

Notes

Funding

This work was supported by a grant from the Shanghai Science and Technology Committee (No.18DZ2290900).

Compliance with ethical standards

Conflict of interest

Juan Wang declares that she has no conflict of interest. Shumei Ma declares that she has no conflict of interest. Xiuhua Chen declares that she has no conflict of interest. Sanqi Zhang declares that he has no conflict of interest. Zhiyong Wang declares that he has no conflict of interest. Qibing Mei declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

Informed constent was obtained from all individual participants included in this study.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.China State Key Laboratory of New Drug & Pharmaceutical Process, Center for Pharmacological Evaluation and ResearchShanghai Institute of Pharmaceutical IndustryShanghaiChina
  2. 2.Department of Medicinal Chemistry, School of Pharmacy, Health Science CenterXi’an Jiaotong UniversityXi’anChina

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