Abstract
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.
Highlights
Cancer is the second largest life-threatening disease in the world after cardiovascular diseases[1]
Effect of test chemicals on cell viability in the cell lines: All the test chemicals-ITB, Cu (II) and DSF were tested on MCF-7, MBA-MD-231, HepG2 and HEK-293 cell lines by MTT assay (Fig. 1A)
We found that the proposed compounds were not effective with the breast cancer cell lines, so both cell lines were not included in further studies under the present investigation
Summary
Cancer is the second largest life-threatening disease in the world after cardiovascular diseases[1]. Copper being an active transition element, can act as pro-oxidant or antioxidant depending on the concurrent cellular redox status[6] Tapping this dual nature of this metal for killing the cancer cells has been a hotspot for oncological research for the last three decades[14,15,16,17]. The level of endogenous copper if manipulated in such a way that can orchestrate the cellular redox status at the optimum level; it can trigger many vital pro-apoptotic proteins facilitating the conditions for induction of programmed cell death It can compel the cancer cells to undergo apoptosis to a greater extent that is considered as the most preferred way to kill the such cells. We tested our hypothesis on chemically induced hepatocarcinoma rat models under in vivo studies
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