TY - JOUR
T1 - Redox-Active Quinone Chelators
T2 - Properties, Mechanisms of Action, Cell Delivery, and Cell Toxicity
AU - Polyakov, Nikolay
AU - Leshina, Tatyana
AU - Fedenok, Lidiya
AU - Slepneva, Irina
AU - Kirilyuk, Igor
AU - Furso, Justyna
AU - Olchawa, Magdalena
AU - Sarna, Tadeusz
AU - Elas, Martyna
AU - Bilkis, Itzhak
AU - Weiner, Lev
N1 - Publisher Copyright:
© 2018, Mary Ann Liebert, Inc.
PY - 2018/5/20
Y1 - 2018/5/20
N2 - Significance: Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity remains a high priority. Recent Advances: Anthracycline antibiotics (AAs), for example, doxorubicin, daunomycin, and mitomycin C, belong to an important family of antitumor agents widely used in chemotherapy. These compounds are all quinones. They are, thus, capable of being reduced by appropriate chemicals or reductases. One of their important properties is that under aerobic conditions their reduced forms undergo oxidation, with concomitant generation of reactive oxygen species (ROS), namely, superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. The presence of metal ions is essential for the generation of ROS by AAs in biological systems. Critical Issues: A fundamental shortcoming of the AAs is their high cardiotoxicity. We have proposed, and experimentally realized, a new type of quinones that is capable of coordinating metal ions. We have demonstrated in vitro that they can be reduced by electron transfer chains and glutathione with concomitant generation of ROS. They can also produce ROS under photo-excitation. The mechanisms of these reactions have been characterized by using nuclear magnetic resonance and electron paramagnetic resonance. Future Directions: To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 28, 1394-1403.
AB - Significance: Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity remains a high priority. Recent Advances: Anthracycline antibiotics (AAs), for example, doxorubicin, daunomycin, and mitomycin C, belong to an important family of antitumor agents widely used in chemotherapy. These compounds are all quinones. They are, thus, capable of being reduced by appropriate chemicals or reductases. One of their important properties is that under aerobic conditions their reduced forms undergo oxidation, with concomitant generation of reactive oxygen species (ROS), namely, superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. The presence of metal ions is essential for the generation of ROS by AAs in biological systems. Critical Issues: A fundamental shortcoming of the AAs is their high cardiotoxicity. We have proposed, and experimentally realized, a new type of quinones that is capable of coordinating metal ions. We have demonstrated in vitro that they can be reduced by electron transfer chains and glutathione with concomitant generation of ROS. They can also produce ROS under photo-excitation. The mechanisms of these reactions have been characterized by using nuclear magnetic resonance and electron paramagnetic resonance. Future Directions: To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 28, 1394-1403.
KW - anticancer
KW - cells
KW - metals
KW - photosensitizers
KW - quinines
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=85045503855&partnerID=8YFLogxK
U2 - 10.1089/ars.2017.7406
DO - 10.1089/ars.2017.7406
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C2 - 29161882
AN - SCOPUS:85045503855
SN - 1523-0864
VL - 28
SP - 1394
EP - 1403
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 15
ER -