New potential biomarker for stratification of patients for pharmacological vitamin C in adjuvant settings of cancer therapy

Bakalova, Rumiana; Zhelev, Zhivko; Miller, T.; Aoki, Ichio; Higashi, Tatsuya

doi:10.1016/j.redox.2019.101357

Cited by 23 publications

(26 citation statements)

References 64 publications

(153 reference statements)

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“…High amounts of NADH and succinate cannot exist unless the “Q pool” is overreduced. This is a very important biochemical/physiological phenomenon, distinguishing cancer cells from normal cells [ 126 ]. Studies on ischemia-reperfusion injury (IRI) have demonstrated that the phenomenon of overcharged “Q-pools” leads to overproduction of superoxide by complex I and complex III [ 127 ].…”

Section: Discussionmentioning

confidence: 99%

“…We assume that the ability of normal cells to convert menadione to vitamin K2 (which has a membrane binding tail) is diminished or absent for cancer cells due to the downregulation of UBIAD1 (TERE1) [ 92 , 93 ]. Combined with relatively low intracellular levels of ascorbate and balanced “Q-pools” within properly functioning mitochondria [ 67 , 126 ], this set of favorable factors protects nontransformed cells from the harmful effects of the M/A.…”

Section: Discussionmentioning

confidence: 99%

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Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Bakalova

Semkova

Ivanova

et al. 2020

Oxidative Medicine and Cellular Longevity

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Redox-active substances and their combinations, such as of quinone/ascorbate and in particular menadione/ascorbate (M/A; also named Apatone®), attract attention with their unusual ability to kill cancer cells without affecting the viability of normal cells as well as with the synergistic anticancer effect of both molecules. So far, the primary mechanism of M/A-mediated anticancer effects has not been linked to the mitochondria. The aim of our study was to clarify whether this “combination drug” affects mitochondrial functionality specifically in cancer cells. Studies were conducted on cancer cells (Jurkat, Colon26, and MCF7) and normal cells (normal lymphocytes, FHC, and MCF10A), treated with different concentrations of menadione, ascorbate, and/or their combination (2/200, 3/300, 5/500, 10/1000, and 20/2000 μM/μM of M/A). M/A exhibited highly specific and synergistic suppression on cancer cell growth but without adversely affecting the viability of normal cells at pharmacologically attainable concentrations. In M/A-treated cancer cells, the cytostatic/cytotoxic effect is accompanied by (i) extremely high production of mitochondrial superoxide (up to 15-fold over the control level), (ii) a significant decrease of mitochondrial membrane potential, (iii) a decrease of the steady-state levels of ATP, succinate, NADH, and NAD+, and (iv) a decreased expression of programed cell death ligand 1 (PD-L1)—one of the major immune checkpoints. These effects were dose dependent. The inhibition of NQO1 by dicoumarol increased mitochondrial superoxide and sensitized cancer cells to M/A. In normal cells, M/A induced relatively low and dose-independent increase of mitochondrial superoxide and mild oxidative stress, which seems to be well tolerated. These data suggest that all anticancer effects of M/A result from a specific mechanism, tightly connected to the mitochondria of cancer cells. At low/tolerable doses of M/A (1/100-3/300 μM/μM) attainable in cancer by oral and parenteral administration, M/A sensitized cancer cells to conventional anticancer drugs, exhibiting synergistic or additive cytotoxicity accompanied by impressive induction of apoptosis. Combinations of M/A with 13 anticancer drugs were investigated (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103). Low/tolerable doses of M/A did not induce irreversible cytotoxicity in cancer cells but did cause irreversible metabolic changes, including: (i) a decrease of succinate and NADH, (ii) depolarization of the mitochondrial membrane, and (iii) overproduction of superoxide in the mitochondria of cancer cells only. In addition, M/A suppressed tumor growth in vivo after oral administration in mice with melanoma and the drug downregulated PD-L1 in melanoma cells. Experimental data suggest a great potential for beneficial anticancer effects of M/A through increasing the sensitivity of cancer cells to conventional anticancer therapy, as well as to the immune system, while sparing normal cells. We hypothesize that M/A-mediated anticancer effects are triggered by redox cycling of both substances, specifically within dysfunctional mitochondria. M/A may also have a beneficial effect on the immune system, making cancer cells “visible” and more vulnerable to the native immune response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Bakalova

Semkova

Ivanova

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…This suggests that L-AA at pharmacological concentrations may serve as an anti-cancer drug. However, it is not well-clear why L-AA kills some cancer cells through mechanisms related to hydrogen peroxide but has little effect on normal cells (23).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and Applications of the Anti-cancer Effect of Pharmacological Ascorbic Acid in Cervical Cancer Cells

Liu

Chen

et al. 2020

Front. Oncol.

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In recent years, L-ascorbic acid (L-AA), or vitamin C, has been attracting attention as a potential anticancer drug that mediates hydrogen peroxide-induced oxidation and ten-eleven translocation 2-catalyzed DNA demethylation. However, the precise mechanism by which L-AA acts remains unclear. We examined the cytotoxic effects of L-AA or sodium ascorbate in human cervical carcinoma cells by assessing cell viability, expression of cell cycle-related mRNAs and proteins, and mitochondrial functions, and by performing flow cytometric analyses of cell cycle profiles, apoptosis, cell proliferation, and production of reactive oxygen species (ROS). We later tested the effects of ascorbates in combination with two first-line chemotherapeutic drugs, cisplatin, and doxorubicin. At pharmacological concentrations (1-10 mM), L-AA increased ROS levels; decreased levels of several cell cycle-related proteins, including p53, p21, cyclin D1, and phosphorylated histone 3 at serine residue 10; induced DNA damage, as indicated by changes in γH2A.x; decreased levels of the anti-oxidative transcription factor Nrf2; and increased levels of catalase, superoxide dismutase 1, and endoplasmic reticulum stress-related indicators, such as the p-eIF2α/eIF2α ratio and CHOP levels. L-AA also promoted cell proliferation and induced apoptosis and mitochondrial dysfunction. Finally, L-AA increased the susceptibility of HeLa cells to cisplatin and doxorubicin. These findings provide insight into how the adjustment of the cellular ROS status through L-ascorbate (L-AA or sodium ascorbate) administration could potentially synergistically enhance the efficacy of cancer therapies.

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“…The soluble isoform of CYB5R3 is exclusive to erythrocytes [ 372 ], whereas the membrane-bound isoform is anchored to MOM, ER, and plasma membrane lipid rafts [ 368 , 373 , 374 ]. Importantly, the OMM-bound CYB5R3 enzyme, ubiquitously expressed in all mammalian cells, is functionally attached to the voltage-dependent anion channel 1 (VDAC1), one of the most prevalent proteins located in the OMM [ 375 , 376 ].…”

Section: The Interdependence Between Membranes and Membraneless Organellesmentioning

confidence: 99%

“…Over stimulation and clustering of CYB5R3 induced oxidative stress-mediated apoptosis of cerebellar granule neurons [ 386 ]. Independent of respiratory chain activities, the ascorbate-dependent NADH: cytochrome c oxidoreductase oxidation of NADH at CYB5R3 centers in lipid rafts is also a major source of extracellular superoxide [ 376 , 387 , 388 , 389 , 390 ] that can initiate lipid peroxidation. In Wistar rats, the deregulation of CYB5R3 promptly triggers apoptosis due to the overproduction of superoxide anions at neuronal plasma membranes [ 368 , 387 ].…”

Section: The Interdependence Between Membranes and Membraneless Organellesmentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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New potential biomarker for stratification of patients for pharmacological vitamin C in adjuvant settings of cancer therapy

Cited by 23 publications

References 64 publications

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

Mechanisms and Applications of the Anti-cancer Effect of Pharmacological Ascorbic Acid in Cervical Cancer Cells

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

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