Bakalova, Rumiana; Lazarova, Dessislava; Sumiyoshi, Akira; Shibata, Sayaka; Zhelev, Zhivko; Nikolova, Biliana; Semkova, Severina; Vlaykova, Tatyana; Aoki, Ichio

Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy

2023

International Journal of Molecular Sciences, 24(9), Article number 8435

Bakalova, R., Lazarova, D., Sumiyoshi, A., Shibata, S., Zhelev, Z., Nikolova, B., Semkova, S., Vlaykova, T., Aoki, I., & Higashi, T. (2023). Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy. International Journal of Molecular Sciences, 24(9), 8435. https://doi.org/10.3390/ijms24098435

DOI: 10.3390/ijms24098435 [other]

Article

eng

ascorbate; cancer; mitochondria; oxidative stress; prenylation; quinones; redox-cycling

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.