2. Academic Validation
  3. Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models

Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models

  • Br J Cancer. 2018 Apr;118(7):972-984. doi: 10.1038/s41416-018-0008-y.
Shu Shimada 1,  Yoshimitsu Akiyama 2,  Kaoru Mogushi 2 3,  Mari Ishigami-Yuasa 4,  Hiroyuki Kagechika 4,  Hiromi Nagasaki 2,  Hiroshi Fukamachi 2,  Yasuhito Yuasa 2,  Shinji Tanaka 5 6
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].
  • 2 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
  • 3 Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
  • 4 Chemical Biology Screening Center, and Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
  • 5 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].
  • 6 Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. [email protected].
PMID: 29527007 DOI: 10.1038/s41416-018-0008-y
Abstract

Background: Diffuse-type gastric Cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells.

Methods: We derived mouse gastric Cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents.

Results: We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing Apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric Cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo.

Conclusions: These findings may lead to the development of novel therapeutic strategies targeting DGC.

Figures
Products