Restrained management of copper level enhances the antineoplastic activity of imatinib in vitro and in vivo

• Published in: Scientific reports Vol. 8; no. 1; pp. 1682 - 17
• Main Authors: Hassan, Iftekhar, Khan, Azmat Ali, Aman, Shazia, Qamar, Wajhul, Ebaid, Hossam, Al-Tamimi, Jameel, Alhazza, Ibrahim M., Rady, Ahmed M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.01.2018; Nature Publishing Group
• Subjects: 13/106; 13/2; 14; 14/63; 631/67/1059; 631/67/2195; 64; 82; 82/80; 96/1; 96/106; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Cancer; Caspase; Caspase-3; Caspase-7; Cell culture; Cell Survival - drug effects; Chemotherapy, Adjuvant - methods; Copper; Copper - metabolism; Copper chloride; Disulfiram; Disulfiram - metabolism; Drug Synergism; Humanities and Social Sciences; Imatinib; Imatinib Mesylate - administration & dosage; Imatinib Mesylate - pharmacology; Metabolism - drug effects; multidisciplinary; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - drug therapy; Rats; Science; Science (multidisciplinary); Targeted cancer therapy; Treatment Outcome; Tumor cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19410-1

The present study was designed to investigate if elevated copper level can be targeted to enhance the efficacy of a significant anticancer drug, imatinib (ITB). The antineoplastic activity of this drug was assessed in the HepG2, HEK-293, MCF-7 and MDA-MD-231 cells targeting elevated copper level as their common drug target. The cell lines were treated with the different doses of copper chloride (Cu II) and disulfiram (DSF) alone as well as in their combinations with the drug for 24 h in standard culture medium and conditions. The treated cells were subjected to various assays including MTT, PARP, p-53, caspase-7, caspase-3, LDH and single cell electrophoresis. The study shows that DSF and Cu (II) synergizes the anticancer activity of ITB to a significant extent in a dose-specific way as evidenced by the combinations treated groups. Furthermore, the same treatment strategy was employed in cancer-induced rats in which the combinations of ITB-DSF and ITB-Cu II showed enhanced antineoplastic activity as compared to ITB alone. However, DSF was more effective than Cu (II) as an adjuvant to the drug. Hence, restrained manipulation of copper level in tumor cells can orchestrate the redox and molecular dispositions inside the cells favoring the induction of apoptosis.