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Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer
- Source :
- Hypoxia
- Publication Year :
- 2016
- Publisher :
- Dove Press, 2016.
-
Abstract
- Dimple R Bhatia,Padma Thiagarajan School of Biosciences and Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India Aim: This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC-0941 and BEZ-235.Materials and methods: All hypoxic exposures were carried out at 1% O2/5% CO2. Antiproliferation activity was evaluated by 48hours propidium iodide and 14days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically.Results: In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor-1α (HIF-1α) levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia.Conclusion: Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy. Keywords: GDC-0941, BEZ-235, anticancer, antiproliferation
- Subjects :
- Oncology
Sorafenib
medicine.medical_specialty
antiproliferation
Colorectal cancer
Glucose uptake
GDC-0941
Pharmacology
anticancer
030226 pharmacology & pharmacy
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cyclin D1
Internal medicine
medicine
Propidium iodide
Clonogenic assay
Hypoxia
PI3K/AKT/mTOR pathway
Original Research
BEZ-235
Hypoxia (medical)
medicine.disease
chemistry
030220 oncology & carcinogenesis
medicine.symptom
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 23241128
- Database :
- OpenAIRE
- Journal :
- Hypoxia
- Accession number :
- edsair.doi.dedup.....cf7ec62ca8c2ae896ea5b468de4be8df