In vitro assessment of antitumor activities of the PI3K/mTOR inhibitor GSK2126458

Cancer Cell International

Saeeda Almarzooqi¹  Abdul-Kader Souid³  Mohamed Al Bashir⁴  Muna Al Ayyan²  Alia Albawardi¹ 

[1] Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates;Surgery Department, Tawam Hospital, Al Ain, United Arab Emirates;Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates;Department of Surgery, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

关键词: Cellular respiration;    Caspases;    Cytotoxicity;    mTOR;    PI3K;    GSK2126458;   

Others  :  1121657
DOI  :  10.1186/s12935-014-0090-z

 received in 2014-04-01, accepted in 2014-09-01,  发布年份 2014

【 摘 要 】

Background

Up-regulation of the PI3K/mTOR (phosphatidylinositol-3′ kinase/mammalian target of rapamycin) signaling is common in carcinoma. Consistently, targeting these molecules has been shown to halt the growth of many tumors. The main purpose of this study was to develop surrogate biomarkers of the antitumor activity of PI3K/mTOR inhibitors.

Methods

Fragments from eight tumors were collected immediately after resection in ice-cold RPMI gassed with 95% O₂ :5% CO₂. Viability was determined by measuring tumor cellular respiration (mitochondrial O₂ consumption). The specimens were incubated at 37°C with and without 50 nM GSK2126458 (a highly potent and selective inhibitor of PI3K/mTOR) for 90 min. The tissue was then processed for histology, measurement of intracellular caspase-3 activity (using the caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin), and immunohistochemical detection of the apoptotic biomarkers caspase-3, cytochrome C, and annexin A2.

Results

GSK2126458 induced morphologic changes in four tumors (two invasive ductal carcinomas, one invasive lobular carcinoma, and one ovarian dysgerminoma), intracellular caspase-3 activity in three tumors (two invasive ductal carcinomas and one poorly differentiated signet ring adenocarcinoma of gastric origin), and immunohistochemical evidence of apoptosis in at least four tumors (three invasive ductal carcinomas and one adenocarcinoma of gastric origin). Two tumors (ovarian serous carcinoma and moderately differentiated adenocarcinoma of colorectal origin) demonstrated no treatment effect.

Conclusion

These preliminary results demonstrate the feasibility of using in vitro biomarkers for detecting antitumor activities of the rapidly emerging PI3K/mTOR inhibitors.

【 授权许可】

   
2014 Albawardi et al.; licensee BioMed Central Ltd.

【 图 表 】

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