Newly Synthesized Doxorubicin Complexes with Selected Metals—Synthesis, Structure and Anti-Breast Cancer Activity

Abstract

Doxorubicin (DOX) is very effective chemotherapeutic agent, however it has several major drawbacks. Therefore the motivation for developing novel drug complexes as anticancer agents with different mechanism of action has arisen. The aim of the present study was to evaluate the influence of newly synthesized DOX complexes with selected metals (Mg, Mn, Co, Ni, Fe, Cu, Zn) on apoptosis, cell cycle, viability, proliferation and cytotoxicity in the breast cancer cell line MCF-7. Complexation of DOX with metals has likewise been the subject of our research. The current work showed that the tested bivalent metals at a given pH condition formed metal:DOX complexes in a ratio of 2:1, while iron complexes with DOX in a ratio of 3:1. The studies also showed that selected metal-DOX complexes (Mg-DOX, Mn-DOX, Ni-DOX) at 0.5 µM concentration significantly decreased cell viability and proliferation, however they increased caspase 7 activity. Results also indicated that studied metal-DOX complexes showed high cytotoxicity in MCF-7 cells. Therefore they were chosen for cell cycle check-points and apoptosis/necrosis analysis studied by flow cytometry. Obtained results suggest that doxorubicin complexed by specified metals can be considered as a potential anti-breast cancer agent, which is characterized by a higher efficacy than a parent drug.

Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer

“…In support of this, deletion of the 4 amino-terminal octarepeats resulted in a truncated PrP C protein, restoring sensitivity to doxorubicin in gastric cancer cells (23). Our results suggest that PrP C is able to efficiently complex doxorubicin, as opposed to epirubicin, where access to C5/C6 is restricted by hydrogen bonding from the hydroxyl group on the amino sugar moiety (15,17,22). This interaction is potentially supported by the tumor microenvironment, given that serum copper levels measured in breast cancer patients are twice those of age-matched healthy controls (24).…”

“…Complexing of doxorubicin and PrP C requires free copper ions. Interestingly, PrP C and anthracyclines bind transition metals in physiologic conditions, and there is evidence for biochemical complexing of both to copper (11,15). The highly conserved PrP C octarepeat region contains 6 binding domains that are highly selective for copper and zinc over other divalent metals ( Figure 5A).…”

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“…This functional disruption leads to ultrastructural pathologic changes such as mitochondrial swelling and myelin figures within the mitochondria 26 . In 1980 May et al, demonstrated that doxorubicin had a strong affinity for iron, and it suggests that cellular damage induced by doxorubicin may be mediated by iron -doxorubicin complex 27 . Subsequent studies followed on this hypothesis revealed that this iron complex could cause lipid peroxidation through its interactions with the negatively-charged membranes 28 .…”

Possible Mechanisms of the Prevention of Doxorubicin Toxicity by Cichoric Acid—Antioxidant Nutrient

“…An example of such compound with proved prooxidant activity is Doxorubicin (DOX). DOX is an effective anticancer agent from anthracycline antibiotic group, which has a large spectrum of activity and it is being used alone or in combination to treat a variety of tumors, both haematological and solid, such as breast cancer [ 10 , 11 ]. It inhibits cell proliferation, induces oxidative stress, inhibits topoisomerase II, and finally leads to the cell death mainly through apoptosis [ 12 , 13 , 14 ].…”

“…This Fe-DOX complex is able to reduce oxygen to hydrogen peroxide and other free radicals. In our previous experiment regarding DOX influence on breast cancer cells we revealed that DOX-metal complexes are even more efficient than a parent drug [ 10 , 17 ].…”