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Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells.
Radiat Res 2019RR

Abstract

Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of "metalloenediynes" can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that "tuning" of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating.

Authors+Show Affiliations

Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Chemistry, Indiana University, Bloomington, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Indiana.Department of Chemistry, Indiana University, Bloomington, Indiana.Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31800359

Citation

Garrett, Joy E., et al. "Enhancement of Cytotoxicity of Enediyne Compounds By Hyperthermia: Effects of Various Metal Complexes On Tumor Cells." Radiation Research, 2019.
Garrett JE, Metzger E, Schmitt K, et al. Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells. Radiat Res. 2019.
Garrett, J. E., Metzger, E., Schmitt, K., Soto, S., Northern, S., Kryah, L., ... Dynlacht, J. R. (2019). Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells. Radiation Research, doi:10.1667/RR15433.1.
Garrett JE, et al. Enhancement of Cytotoxicity of Enediyne Compounds By Hyperthermia: Effects of Various Metal Complexes On Tumor Cells. Radiat Res. 2019 Dec 4; PubMed PMID: 31800359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells. AU - Garrett,Joy E, AU - Metzger,Erin, AU - Schmitt,Katelyn, AU - Soto,Sarai, AU - Northern,Samantha, AU - Kryah,Laura, AU - Irfan,Misbah, AU - Rice,Susan, AU - Brown,Mary, AU - Zaleski,Jeffrey M, AU - Dynlacht,Joseph R, Y1 - 2019/12/04/ PY - 2019/12/5/entrez PY - 2019/12/5/pubmed PY - 2019/12/5/medline JF - Radiation research JO - Radiat. Res. N2 - Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of "metalloenediynes" can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that "tuning" of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating. SN - 1938-5404 UR - https://www.unboundmedicine.com/medline/citation/31800359/Enhancement_of_Cytotoxicity_of_Enediyne_Compounds_by_Hyperthermia:_Effects_of_Various_Metal_Complexes_on_Tumor_Cells DB - PRIME DP - Unbound Medicine ER -