**6. Conclusion**

Anthracyclines are widely used as antineoplastic agents owing to their great anticancer potential. There are several mechanisms proposed by which anthracyclines exert their cytotoxic effect. These drugs mostly act as DNA intercalators and halt vital functions like transcription and replication of cells. DNA damage by topoisomerase II poisoning, oxidative stress, and by forming anthracycline-DNA adduct are other proposed mechanism of anthracycline action. Despite their

*Advances in Precision Medicine Oncology*

**4. Anthracycline resistance**

Doxorubicin has a strong affinity for Fe+3 ions and the reaction of ferric ions with hydroxyl and ketone groups of doxorubicin results in a free radical complex of doxorubicin-Fe+2 [33]. The interaction between the negatively charged cell membranes and as this positively charged doxorubicin-Fe complex consequences in lipid peroxidation [33, 34]. Normally the level of iron is quite low in cells and usually, at this low level, doxorubicin cannot interact with iron [29]. The balance of iron is maintained by some transport proteins in the cell and according to some recent studies, doxorubicin disturbs this balance and as a result accumulation of iron occurs in mitochondria [34, 35]. Doxorubicin also interacts with the Fe/S group of iron regulatory protein IRP1 and affects its post-translational modification due to which function of IRP1 is affected and its binding affinity to IRE (iron response element) becomes low resulting in an increased amount of iron in the cell [33]. Mitoferrin, a mitochondrial carrier protein that helps in the entry of iron into the mitochondria and another transfer protein mABC1 export out the iron from mitochondria. Doxorubicin affects the functioning of mABC1 protein due to which it stops the export of iron out of the mitochondria while mitoferrin functions normally and as a result amount of free iron increases inside mitochondria [36].

Along with cardiotoxicity, anthracyclines treatment also induce anthracycline resistance even at the desired cumulative dose [37]. Resistance to drugs can be either natural or can be acquired. Natural resistance is detected in some cells even before the administration of the drug. While the acquired one occurs after the administration of the drug. Several mechanics of drug resistance responsible for the incidence of drug-resistance which are: change in ATP- binding cassette [ABC] related drug efflux and accumulation, qualitative and quantitative changes in topoisomerase II, p53 activity, overexpression of ROS scavenging enzymes, etc. ABC (ATP- binding cassette) transporter proteins are considered as the primary cause of anthracycline related drug resistance [R]. P-glycoprotein (Pgp) is one of the ABC proteins believed to induce anthracycline resistance by drug efflux, inhibition of influx, and drug accumulation inside the cell [38]. Anthracycline interacts with Pgp which causes the active efflux of anthracycline from the cell through its transmembrane domain. Pgp is encoded by the mdr1 gene which becomes active in case of cell differentiation under any chemical or environmental effect. As the anthracycline interacts with the plasma membrane, Pgp recognizes it and exports it out. So, the increased level of

Pgp creates an imbalance between the export and import of the drug.

towards anthracyclines resistance in cells.

**5. Anthracycline analogs**

Moreover, alteration in topoisomerase II activity either quantitative i.e. decrease

Several studies were conducted to understand the effect of structural changes in anthracyclines on their antitumor efficacy. Modification of anthracyclines has

in the number of enzyme or qualitative i.e. alteration in the normal activity of enzyme due to mutation or other reason can give resistance to cell against further doses of anthracyclines. Anthracycline mediated cell apoptosis also depends on the expression of p53. So, inactivation or down regulation of p53 can give rise to drug resistance [38]. SOD, GSH, catalase are the scavengers of ROS and their over expression can also impart anthracycline resistance during cytotoxicity [39]. An increase in the repair of the DNA damage caused by anthracyclines also contributes

**162**

widespread usage in cancer treatment, their administration consequences in certain adverse side effects including cardiotoxicity that limits their clinical use. Therefore, further elucidation of the mechanism by which anthracycline drugs exert their cytotoxic effect becomes extremely important. Structural*, in silico* molecular docking/MD simulations studies and their correlation with the cytotoxic effect provide significant information for the development of structure-based analogs. The synthesis of novel structure-based anthracycline analogs should be continued to get an analog with better efficacy and minimum side effects. The development of an analog that can reverse the effect of drug resistance as well as reduce dosedependent toxicity is essential.
