**4. Anthracycline resistance**

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.

Moreover, alteration in topoisomerase II activity either quantitative i.e. decrease 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 towards anthracyclines resistance in cells.

### **5. Anthracycline analogs**

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

**163**

**6. Conclusion**

*Molecular-Level Understanding of the Anticancer Action Mechanism of Anthracyclines*

a significant impact on their antitumor activity as well as on their side effects. Therefore, a comprehensive study on understanding the effect of specific structural modifications in anthracyclines to its antitumor potential and efficacy leads to the development of better analogs. Subtle modifications in the chemical structure of anthracyclines had a significant impact on the rate of drug penetration into the nucleus [40]. Doxorubicin and it semisynthetic analog epirubicin prepared by epimerization at C-4′ sugar display different antitumor potential (**Figures 1** and **2**). Moreover, epirubicin causes less cardiac damage as compared to its parent compound. Similarly, the removal of the methoxy group in the anthraquinone structure of daunorubicin results in the formation of idarubicin, considered to a better analog with a broad spectrum of antitumor potential as compared to daunorubicin

Numerous studies were undertaken in preparation for better analogs. One such study was done with the aim of preparing a better daunorubicin analog that was prepared and their level of cytotoxicity, DNA damaging property, cellular uptake of daunorubicin analogs was investigated to find an anthracycline that can overcome drug resistance. Anthracycline derivatives display different action mechanisms in causing DNA lesions in various human cancer cell lines as well as in their resistant sublines [41]. It was hypothesized that the replacing primary amino group at the C3 position of the daunosamine moiety by a trisubstituted amidino group might help

Shaul et al. investigated the subcellular localization as well as their cytotoxic effect of anthracyclines and their analogs in various cell lines [42]. Association between the chemical structure of different anthracyclines and their subcellular distribution and their function was investigated in cancer cell lines. Confocal microscopy experiments were done to study subcellular localization of anthracyclines and their analogs. Fluorescent DNA intercalator displacement experiments conducted for studying the intercalative properties demonstrated that the DNA intercalation property of anthracycline was not related to their cytotoxic effect. Structural information on the binding of anthracycline drugs with the target

X-ray crystallographic and NMR (nuclear magnetic resonance) spectroscopic studies on anthracyclines-target complex have been conducted in the past and provide significant information that helps in the rational designing of drugs. Proceeding in similar lines, Yan et al. investigated the interactions of doxorubicin and its derivatives with DNA using resonance Raman and surface-enhanced resonance Raman scattering spectroscopy and provide significant details on anthracycline binding with DNA [43]. Spectroscopic techniques like Fourier transform infrared spectroscopy (FTIR), circular dichroism, fluorescence provided significant information binding properties of anthracyclines with nucleic acid [44–48]. Conformational studies on anthracycline-nucleic acid complex using computational methods like molecular dynamics (MD) simulations also contributes significantly

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

*DOI: http://dx.doi.org/10.5772/intechopen.94180*

(**Figures 1** and **2**).

in overcoming drug resistance [41].

molecule helps in the development of effective drugs.

to the development of the better anthracycline alternative.

#### *Molecular-Level Understanding of the Anticancer Action Mechanism of Anthracyclines DOI: http://dx.doi.org/10.5772/intechopen.94180*

a significant impact on their antitumor activity as well as on their side effects. Therefore, a comprehensive study on understanding the effect of specific structural modifications in anthracyclines to its antitumor potential and efficacy leads to the development of better analogs. Subtle modifications in the chemical structure of anthracyclines had a significant impact on the rate of drug penetration into the nucleus [40]. Doxorubicin and it semisynthetic analog epirubicin prepared by epimerization at C-4′ sugar display different antitumor potential (**Figures 1** and **2**). Moreover, epirubicin causes less cardiac damage as compared to its parent compound. Similarly, the removal of the methoxy group in the anthraquinone structure of daunorubicin results in the formation of idarubicin, considered to a better analog with a broad spectrum of antitumor potential as compared to daunorubicin (**Figures 1** and **2**).

Numerous studies were undertaken in preparation for better analogs. One such study was done with the aim of preparing a better daunorubicin analog that was prepared and their level of cytotoxicity, DNA damaging property, cellular uptake of daunorubicin analogs was investigated to find an anthracycline that can overcome drug resistance. Anthracycline derivatives display different action mechanisms in causing DNA lesions in various human cancer cell lines as well as in their resistant sublines [41]. It was hypothesized that the replacing primary amino group at the C3 position of the daunosamine moiety by a trisubstituted amidino group might help in overcoming drug resistance [41].

Shaul et al. investigated the subcellular localization as well as their cytotoxic effect of anthracyclines and their analogs in various cell lines [42]. Association between the chemical structure of different anthracyclines and their subcellular distribution and their function was investigated in cancer cell lines. Confocal microscopy experiments were done to study subcellular localization of anthracyclines and their analogs. Fluorescent DNA intercalator displacement experiments conducted for studying the intercalative properties demonstrated that the DNA intercalation property of anthracycline was not related to their cytotoxic effect. Structural information on the binding of anthracycline drugs with the target molecule helps in the development of effective drugs.

X-ray crystallographic and NMR (nuclear magnetic resonance) spectroscopic studies on anthracyclines-target complex have been conducted in the past and provide significant information that helps in the rational designing of drugs. Proceeding in similar lines, Yan et al. investigated the interactions of doxorubicin and its derivatives with DNA using resonance Raman and surface-enhanced resonance Raman scattering spectroscopy and provide significant details on anthracycline binding with DNA [43]. Spectroscopic techniques like Fourier transform infrared spectroscopy (FTIR), circular dichroism, fluorescence provided significant information binding properties of anthracyclines with nucleic acid [44–48]. Conformational studies on anthracycline-nucleic acid complex using computational methods like molecular dynamics (MD) simulations also contributes significantly to the development of the better anthracycline alternative.
