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Investigational New Drugs

, Volume 37, Issue 2, pp 252–261 | Cite as

Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types

  • Cijo George Vazhappilly
  • Ekram Saleh
  • Wafaa Ramadan
  • Varsha Menon
  • Aya Mudhafar Al-Azawi
  • Hamadeh Tarazi
  • Hajjaj Abdu-Allah
  • Abdel-Nasser El-Shorbagi
  • Raafat El-AwadyEmail author
PRECLINICAL STUDIES

Summary

Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate–4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 μM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.

Keywords

SHP2 RAS/MAPK AKT STAT3 Phosphatase inhibitors 

Notes

Funding

The work was supported by AlJalila Foundation for Medical Education and Research, United Arab Emirates [grant number. AJF201612]

Compliance with Ethical Standards

Conflict of Interest

Author CV declares that he has no conflict of interest. Author ES declares that he has no conflict of interest. Author WR declares that he has no conflict of interest. Author VM declares that he has no conflict of interest. Author AA declares that he has no conflict of interest. Author HT declares that he has no conflict of interest. Author HA declares that he has no conflict of interest. Author AE declares that he has no conflict of interest. Author RE declares that he has no conflict of interest

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

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Copyright information

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

Authors and Affiliations

  • Cijo George Vazhappilly
    • 1
  • Ekram Saleh
    • 1
    • 2
  • Wafaa Ramadan
    • 1
  • Varsha Menon
    • 1
  • Aya Mudhafar Al-Azawi
    • 1
  • Hamadeh Tarazi
    • 1
    • 3
  • Hajjaj Abdu-Allah
    • 4
  • Abdel-Nasser El-Shorbagi
    • 3
    • 4
  • Raafat El-Awady
    • 1
    • 3
    Email author
  1. 1.Sharjah Institute for Medical ResearchUniversity of SharjahSharjahUnited Arab Emirates
  2. 2.Cancer Biology Department, National Cancer InstituteCairo UniversityCairoEgypt
  3. 3.College of PharmacyUniversity of SharjahSharjahUnited Arab Emirates
  4. 4.Medicinal Chemistry Department, College of PharmacyAssuit UniversityAssuitEgypt

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