Although generation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for anti-tumor activity, they make these drugs cardiotoxic.
The hydroxy‐9,10‐anthraquinones in anthracyclines form semiquinones and reactive oxygen species (ROS) that help in antitumor activity. ROS generation is cytotoxic to cells but cardiotoxic as well. Carminic acid (CA) with a sugar bound to a hydroxyanthraquinone resembles anthracyclines closely. Role of sugar in anthracyclines was realized from physicochemical parameters of CA that were found to be in between those of anthracyclines and hydroxy‐9,10‐anthraquinones. A Cu(II)complex of CA was prepared and its structure attempted from powder X‐ray diffraction. Studies with DNA revealed unlike CA, the complex did not show decrease in binding constant with increase in the pH of the medium. DNA relaxation assay showed the complex as a dual inhibitor of human DNA topoisomerase I and topoisomerase II stabilizing covalent topoisomerase‐DNA adducts in vitro. Inhibition of growth of ALL‐MOLT‐4 cells was higher for the complex supporting in vitro experiments. An enzyme assay revealed less superoxide formation for the complex suggesting that it might be less cardiotoxic. Decrease in superoxide for the complex does not affect anticancer activity, which was greater than CA.
Quinalizarin
(THAQ), a hydroxy-9,10-anthraquinone analogue of the
family of anthracycline anticancer drugs and an inhibitor of protein
kinase, was observed for its anticancer activity. Because apart from
showing anticancer activity, anthracyclines and their analogues also
show cardiotoxic side effects, believed to be addressed through metal
complex formation; an effort was made to realize this by preparing
a Co
II
complex of THAQ. The aim of this study was to find
out if complex formation leads to a decrease in the generation of
intermediates that are responsible for toxic side effects. However,
because this also meant that efficacy on cancer cells would be compromised,
studies were undertaken on two cancer cell lines, namely, acute lymphoblastic
leukemia (ALL) MOLT-4 and HCT116 cells. The complex decreases the
flow of electrons from NADH to molecular oxygen (O
2
) in
the presence of NADH dehydrogenase forming less semiquinone than THAQ.
It showed increased affinity toward DNA with binding constant values
remaining constant over the physiological pH range unlike THAQ (for
which decrease in binding constant values with increase in pH was
observed). The complex is probably a human DNA topoisomerase I and
human DNA topoisomerase II poison acting by stabilizing the covalent
topoisomerase-cleaved DNA adduct, a phenomenon not observed for THAQ.
Activity of the compounds on cancer cells suggests that THAQ was more
effective on ALL MOLT-4 cells, whereas the complex performed better
on HCT116 cells. Results suggest that the formation of semiquinone
probably dominates the action because of THAQ, whereas the performance
of the complex is attributed to increased DNA binding, inhibition
of topoisomerase, and so forth. Inspite of a decrease in the generation
of superoxide by the complex, it did not hamper efficacy on either
cell line, probably compensated by improved DNA binding and inhibition
of topoisomerase enzymes which are positive attributes of complex
formation. A decrease in superoxide formation suggests that the complex
could be less cardiotoxic, thus increasing its therapeutic index.
Cancer cells with defective DNA decatenation checkpoint can be selectively targeted by the catalytic inhibitors of DNA topoisomerase IIα (topo IIα) enzyme. Upon treatment with catalytic topo IIα inhibitors, cells with defective decatenation checkpoint fail to arrest their cell cycle in G2 phase and enter into M phase with catenated and under-condensed chromosomes resulting into impaired mitosis and eventually cell death. In the present work we analyzed decatenation checkpoint in five different colon cancer cell lines (HCT116, HT-29, Caco2, COLO 205 and SW480) and in one non-cancerous cell line (HEK293T). Four out of the five colon cancer cell lines i.e. HCT116, HT-29, Caco2, and COLO 205 were found to be compromised for the decatenation checkpoint function at different extents, whereas SW480 and HEK293T cell lines were found to be proficient for the checkpoint function. Upon treatment with ICRF193, decatenation checkpoint defective cell lines failed to arrest the cell cycle in G2 phase and entered into M phase without proper chromosomal decatenation, resulting into the formation of tangled mass of catenated and under-condensed chromosomes. Such cells underwent mitotic catastrophe and rapid apoptosis like cell death and showed higher sensitivity for ICRF193. Our study suggests that catalytic inhibitors of topoisomerase IIα are promising therapeutic agents for the treatment of colon cancers with defective DNA decatenation checkpoint.
DNA topoisomerases are important cellular enzymes found in almost all types of living cells (eukaryotic and prokaryotic). These enzymes are essential for various DNA metabolic processes e.g. replication, transcription, recombination, chromosomal decatenation etc. These enzymes are important molecular drug targets and inhibitors of these enzymes are widely used as effective anticancer and antibacterial drugs. However, topoisomerase inhibitors have some therapeutic limitations and they exert serious side effects during cancer chemotherapy. Thus, development of novel anticancer topoisomerase inhibitors is necessary for improving cancer chemotherapy. Nature serves as a repertoire of structurally and chemically diverse molecules and in the recent years many DNA topoisomerase inhibitors have been identified from natural sources. The present review discusses anticancer properties and therapeutic importance of eighteen recently identified natural topoisomerase inhibitors (from the year 2009 to 2015). Structural characteristics of these novel inhibitors provide backbones for designing and developing new anticancer drugs.
Toxicity of azo dyes and theirinteraction with biological systems has either been overlooked or not exploited properly. A CuII complex of 2‐(2‐hydroxyphenylazo)‐indole‐3/‐acetic acid (HPIA) was synthesized to see role of metal ions on azo toxicity. It was characterized with UV‐Vis, IR, EPR, mass spectrometry, elemental and thermogravimetric analysis. Evidence suggest formation of a bis‐azo complex with stability constant logβ=12.88. DFT calculations based on spectroscopic evidence suggest 1:2::CuII:HPIA complex. Enzyme assay on reductive cleavage of the azo bond shows complex forms less amines than HPIA. Binding of complex to DNA was similar to HPIA. As the complex restricts reduction of azo bond to toxic amines and has comparable binding with DNA it could be less cytotoxic. Cis and trans HPIA and the complex were treated to normal HEK293T cells; activity was comparable at low concentrations. When compounds were treated to human colon carcinomaHCT116 cells, ALL MOLT‐4 human leukemia cells and MCF‐7 breast cancer cells activity of the complex was better than cisor trans HPIA. The study revealed complex formation of HPIA with CuII targets carcinoma cellsmore than HPIA.
Desgalactotigonin and oleanolic acid 3-O-β-d-glucuronide were isolated from Chenopodium album and were evaluated for cytotoxic activity against various cancer cell lines.
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