Topoisomerase I and II are essential enzymes in the regulation of DNA topology and super coiling. They are crucial for transcription and replication. Topoisomerase I (topo I) breaks one of the DNA strands. The enzyme relegates the break to restore the DNA with an altered linking number. The only topo I inhibitors to have undergone clinical trials as antitumor drugs are camptothecin and its structural derivatives. Topo II is an enzyme that catalyzes changes in the topology of DNA via a mechanism that involves the transient double-strand breaking and rejoining of phosphodiester bonds. This enzyme plays several key roles in DNA metabolism and chromosome structure, and it is the primary molecular target for a number of potent anticancer drugs such as etoposide. Topo II inhibitors are widely used as antitumor agents. Doxorubicin is a potent human DNA topoisomerase I and topoisomerase II inhibitor.
Doxorubicin, an antibiotic and an anti-cancer chemotherapy agent, inhibits DNA topo I and topo II.
It is a cytotoxic anthracycline antibiotic. Doxorubicin is an anti-cancer chemotherapy agent. Moreover, it is a potent human DNA Topo I and Topo II inhibitor with IC50s of 0.8 μM and 2.67 μM, respectively. Doxorubicin also reduces basal phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase. It also induces apoptosis and autophagy. In addition, it decreases the viability of MCF-10F, MCF-7 and MDA-MB-231 cells in a time- and dose-dependent manner. Doxorubicin also results in Hct-116 human colon carcinoma cells reduction in G0/G1 phase and accumulation in G2 phase. Furthermore, Doxorubicin induces apoptosis by upregulating Bax, caspase-8, and caspase-3 and downregulation of Bcl-2 protein expression.
In summary, anthracycline antibiotic Doxorubicin belongs among the most important antineoplastic agent used in cancer therapy. Doxorubicin activated apoptosis by inducing proteolytic processing of Bcl-2 family, caspases and simultaneously decreased oxidative stress by influencing ROS damage in MCF-7 and MDA-MB-231 cell lines.