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Modulation of Imatinib Cytotoxicity by Selenite in HCT 116 Colorectal Cancer Cells
Author(s) -
AbdelAziz Amal Kamal,
Azab Samar Saad Eldeen,
Youssef Samar Samir,
ElSayed Abeer Mostafa,
ElDemerdash Ebtehal,
Shouman Samia
Publication year - 2015
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12281
Subject(s) - cytotoxicity , imatinib , apoptosis , cancer research , chemistry , colorectal cancer , autophagy , pharmacology , selenium , cell cycle , cancer cell , cancer , medicine , biochemistry , in vitro , myeloid leukemia , organic chemistry
Imatinib is a principal therapeutic agent for targeting colorectal tumours. However, mono‐targeting by imatinib does not always achieve complete cancer eradication. Selenite, a well‐known chemopreventive agent, is commonly used in cancer patients. In this study, we aimed to explore whether selenite can modulate imatinib cytotoxicity in colorectal cancer cells. HCT 116 cells were treated with different concentrations of imatinib and/or selenite for 24, 48 and 72 hr. Imatinib–selenite interaction was analysed using isobologram equation. As indicators of apoptosis, DNA fragmentation, caspase‐3 activity, Bcl‐2 expression were explored. Autophagic machinery was also checked by visualizing acidic vesicular organelles and measuring Beclin‐1 expression. Furthermore, reactive oxygen and nitrogen species were also examined. This study demonstrated that selenite synergistically augmented imatinib cytotoxicity in HCT 116 cells as demonstrated by combination and dose reduction indices. Supranutritional dose of selenite when combined with imatinib induced apoptotic machinery by decreasing Bcl‐2 expression, increasing caspase‐3 activity and subsequently fragmenting DNA and blunted cytoprotective autophagy by decreasing Beclin‐1 expression and autophagosomes formation. Moreover, their combination induced cell cycle S‐phase block, increased total thiol content and reduced nitric oxide levels. In conclusion, selenite synergizes imatinib cytotoxicity through multi‐barrelled molecular targeting, providing a novel therapeutic approach for colorectal cancer.