Pharmacological Strategy for Selective Targeting of Glioblastoma by Redox-active Combination Drug – Comparison With the Chemotherapeutic Standard-of-care Temozolomide

Sumiyoshi, Akira; Shibata, Sayaka; Zhelev, Zhivko; Miller, T.; Lazarova, Dessislava; Zlateva, G.; Aoki, Ichio; Bakalova, Rumiana

doi:10.21873/anticanres.15426

Cited by 5 publications

(7 citation statements)

References 40 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar tendencies were observed in our previous study on an orthotopic GS9L glioblastoma model comparing mice treated intracranially with M/A or temozolomide (TMZ) [ 26 ]. TMZ is the ‘gold standard’ for first-line chemotherapy of patients with glioblastoma [ 27 ].…”

Section: Discussionsupporting

confidence: 87%

“…TMZ is the ‘gold standard’ for first-line chemotherapy of patients with glioblastoma [ 27 ]. The survival of M/A-treated mice was comparable to that of TMZ-treated at the doses we have tested so far, although the effect of M/A on tumor growth was much less pronounced than that of TMZ [ 26 ]. The tumor size decreased markedly within a few days after the intracranial injection of TMZ, but this was accompanied by severe side-effects such as tetraplegia, convulsions, fever, cachexia [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…The survival of M/A-treated mice was comparable to that of TMZ-treated at the doses we have tested so far, although the effect of M/A on tumor growth was much less pronounced than that of TMZ [ 26 ]. The tumor size decreased markedly within a few days after the intracranial injection of TMZ, but this was accompanied by severe side-effects such as tetraplegia, convulsions, fever, cachexia [ 26 ]. The same side-effects have been reported by other authors even with oral administration of the drug [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

et al. 2023

Self Cite

View full text Add to dashboard Cite

Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling ‘mitocans’ such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues. Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX). Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A. Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…Numerous studies show that AA+MD combination selectively targets various cancer cells, including GBM [ 16 , 71 ], over the nontransformed cells of the same origin [ 11 , 17 , 40 , 45 , 55 , 62 , 72 ]. The ability of the combination to preferentially damage cancer cells is attributed to the strong overproduction of mitochondrial superoxide due to MD and AA redox cycling in dysfunctional/overcharged mitochondria, which is typical for cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells

Despotović

Mirčić

Misirlić-Denčić

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.

show abstract

“…Menadione (MD, vitamin K3, 2-methyl-1,4-naphtoquinone) alone, and in combination with ascorbic acid (AA), has been shown to possess significant anticancer activity against different cancer types, including GBM, in vitro and in vivo [20][21][22][23][24][25]. The anticancer effect of both MD and the AA+MD combination is mediated by oxidative stress, namely, cellular quinone reductases metabolize MD to hydroquinone through semiquinone intermediate, producing a superoxide anion.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Akt and JNK Kinase Inhibitors 10-DEBC and SP600125 Potentiate Anti-Glioblastoma Effect of Menadione and Ascorbic Acid Combination in Human U251 Glioblastoma Cells

Despotović,

Janjetović,

Zogović

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, characterized by a highly invasive nature and therapy resistance. Combination of menadione and ascorbic acid (AA+MD) exerts strong ROS-mediated anti-GBM activity in vitro. The objective of this study was to improve AA+MD anti-GBM potential by modulating the activity of Akt and c-Jun N-terminal kinase (JNK), molecules with an important role in GBM development. The effects of Akt and JNK modulation on AA+MD toxicity in U251 human glioblastoma cells were assessed by cell viability assays, flow cytometry, RNA interference and plasmid overexpression, and immunoblot analysis. The AA+MD induced severe oxidative stress, an early increase in Akt phosphorylation followed by its strong inhibition, persistent JNK activation, and U251 cell death. Small molecule Akt kinase inhibitor 10-DEBC enhanced, while pharmacological and genetic Akt activation decreased, AA+MD-induced toxicity. The U251 cell death potentiation by 10-DEBC correlated with an increase in the combination-induced autophagic flux and was abolished by genetic autophagy silencing. Additionally, pharmacological JNK inhibitor SP600125 augmented combination toxicity toward U251 cells, an effect linked with increased ROS accumulation. These results indicate that small Akt and JNK kinase inhibitors significantly enhance AA+MD anti-GBM effects by autophagy potentiation and amplifying deleterious ROS levels.

show abstract

Pharmacological Strategy for Selective Targeting of Glioblastoma by Redox-active Combination Drug – Comparison With the Chemotherapeutic Standard-of-care Temozolomide

Cited by 5 publications

References 40 publications

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells

Pharmacological Akt and JNK Kinase Inhibitors 10-DEBC and SP600125 Potentiate Anti-Glioblastoma Effect of Menadione and Ascorbic Acid Combination in Human U251 Glioblastoma Cells

Contact Info

Product

Resources

About