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Unprenylated quinone-containing pairs showed dose-dependent anticancer effects with superoxide overproduction and accelerated ATP depletion, while normal cells showed only mild, well-tolerated mitochondrial oxidative stress. Coenzyme Q0/ascorbate was most effective in vitro and in vivo, attributed to reduced quinone prenylation, targeted accelerated redox-cycling in impaired cancer mitochondria, and tNOX 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mitochondrial semiquinone production and superoxide, specific accelerated redox-cycling mainly in impaired cancer mitochondria, and downregulation of tNOX.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},376774,1790489235,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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Dessislava Lazarova 2, Akira Sumiyoshi 1, Sayaka Shibata 1, Zhivko Zhelev 3,4, Biliana Nikolova 4, Severina Semkova 4, Tatyana Vlaykova 3, Ichio Aoki 1 and Tatsuya Higashi 1  \nCitation: Bakalova, R.; Lazarova, D.; Sumiyoshi, A.; Shibata, S.; Zhelev, Z.; Nikolova, B.; Semkova, S.; Vlaykova, T.; Aoki, I.; Higashi, T. Redox-Cycling“Mitocans” as Effective New Developments in Anticancer Therapy. Int. J. Mol. Sci. 2023, 24, 8435 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24098435  \nAcademic Editor: Patrizia Bottoni  \n1 Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan  \n2 Faculty of Medicine, Sofia University, St. Kliment Ohridski, 1407 Sofia, Bulgaria  \n3 Faculty of Medicine, Trakia University, 6000 Stara Zagora, Bulgaria  \n4 Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria  \n* Correspondence: bakalova.rumiana@qst.go.jp or [ra_bakalova@yahoo.com](ra_bakalova@yahoo.com)  \nAbstract: Our study proposes a pharmacological strategy to target cancerous mitochondria via redoxcycling “mitocans” such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinonesand ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX.  \nKeywords: quinones; ascorbate; cancer; mitochondria; redox-cycling; prenylation; oxidative stress  \n1. Introduction  \nReceived: 11 March 2023  \nRevised: 20 April 2023  \nAccepted: 28 April 2023  \nPublished: 8 May 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nThe concept of “epigenetic priming” of cells that is under mitochondrial control has revived interest in mitoepigenetic regulation of cancer [1] . Damaged mitochondrial checkpoints and redox imbalance have been shown to cause metabolic reprogramming in the nucleus via reversible or irreversible changes in the methylation and/or acetylation of nuclear genome [1] . In this regard, the development of pharmaceutical strategies to affect mitochondrial function and retrograde (mitochondrial-to-nuclear) signaling pathways offer great potential and hope for effective anticancer therapy.  \n“Mitocans” is a an acronym derived from the terms “mitochondria” and","cbCaigGTbFlptYTw","https://ap.wps.com/l/cbCaigGTbFlptYTw","pdf",2572529,23,"English","# Abstract\n# Introduction","[{\"question\":\"What are redox-cycling “mitocans” and what therapeutic goal do they target?\",\"answer\":\"They are anticancer drugs whose activity comes from targeting mitochondria and disrupting energetic and synthetic functions, aiming to reduce cancer cells’ energy and metabolite supply while suppressing mitochondrial–nuclear interplay.\"},{\"question\":\"How were the quinone/ascorbate (Q/A) redox-pairs evaluated in the study?\",\"answer\":\"Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice, assessing proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox state, tNOX expression, tumor growth, and survival.\"},{\"question\":\"Why do unprenylated quinone/ascorbate pairs show stronger anticancer effects than prenylated forms?\",\"answer\":\"They exhibit stronger dose-dependent effects linked to downregulation of quinone prenylation, increased mitochondrial semiquinone production and superoxide, specific accelerated redox-cycling mainly in impaired cancer mitochondria, and downregulation of tNOX.\"}]","Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy | PDF",1790221129,58]