Redox-Cycling "Mitocans" as Effective New Developments in Anticancer Therapy.

Abstract

Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling "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 quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX.

• Authors: Rumiana Bakalova, Dessislava Lazarova, Akira Sumiyoshi, Sayaka Shibata, Zhivko Zhelev, Biliana Nikolova, Severina Semkova, Tatyana Vlaykova, Ichio Aoki, Tatsuya Higashi
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 9 (May 08 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37176145 (Publication Type: Journal Article)

Chemical References

• quinone
• Superoxides
• Ascorbic Acid
• Quinones
• Adenosine Triphosphate

Topics

• Mice
• Animals
• Superoxides (metabolism)
• Oxidation-Reduction
• Ascorbic Acid (metabolism)
• Quinones (metabolism)
• Neoplasms (metabolism)
• Adenosine Triphosphate (metabolism)