title: Modulation of imatinib cytotoxicity by selenite in HCT116 colorectal cancer cells.
abstract: 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. HCT116 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 HCT116 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.
authors.affiliation: Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Amal Kamal
authors.initials: AK
authors.lastname: Abdel-Aziz
authors.forename: Samar Saad Eldeen
authors.initials: SS
authors.lastname: Azab
authors.forename: Samar Samir
authors.initials: SS
authors.lastname: Youssef
authors.forename: Abeer Mostafa
authors.initials: AM
authors.lastname: El-Sayed
authors.forename: Ebtehal
authors.initials: E
authors.lastname: El-Demerdash
authors.forename: Samia
authors.initials: S
authors.lastname: Shouman
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020887:Selenious Acid / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D001549:Benzamides; D008565:Membrane Proteins; D009589:Nitrogen Oxides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C505407:CASP3 protein, human; D053148:Caspase 3; D020887:Selenious Acid