Delving into the Latest Updates on Ascorbic Acid/Menadione with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Apatone, Apatone-B

Target

NF-κB

Action

inhibitors

Mechanism

NF-κB inhibitors(Nuclear factor NF-kappa-B complex inhibitors), Vitamin C supplements

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases

Active Indication

Joint DiseasesProstatic Cancer

Inactive Indication

EdemaForeign-Body ReactionOsteolysis+ [3]

Originator Organization

Ic Medtech Corp.

Active Organization

Summa Health System (Ohio)

Ic Medtech Corp.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC11H8O2

InChIKeyMJVAVZPDRWSRRC-UHFFFAOYSA-N

CAS Registry58-27-5

View All Structures (2)

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.

01 Oct 2014·Ultrastructural PathologyQ4 · ENGINEERING & TECHNOLOGY

Pro-oxidant Treatment of Human Prostate Carcinoma (DU145) Induces Autoschizis Cell Death: Autophagosomes Build up out of Injured Endomembranes and Mitochondria

Q4 · ENGINEERING & TECHNOLOGY

Article

Author: Jack L. Summers ; Jacques Gilloteaux ; James M. Jamison

One hour after pro-oxidative treatment by either ascorbate (VC), menadione (VK3), or VC: VK3 combination followed by 24-h incubation in culture medium, DU145 human prostate carcinoma cells developed ultrastructural-dependent organelle damage with the sequence Sham > VC > VK3 > VC: VK3. Along the nuclear alterations and the cytoplasm self-excisions reducing cell size, other induced injuries concerned mitochondria and endomembranes that associated with lysosomes. Damaged organelles surrounded by specialized endoplasmic membranes formed autophagosomes out of phagophores that also captured pieces of glycogen-rich cytoplasm. Most autophagosomes amassed in the diminished-size perikarya and corroborated the enhanced cytotoxicity of the VC: VK3 treatment. These accumulations did not initiate cell death, instead were merely signs of excessive "recycling" of damaged organelles. These features may reflect that high lysosomal activities provided foodstuffs in an ultimate strategy of survival of the tumor cells already devastated by reactive oxidative species (ROS) energetic sites. As such they became transient markers preceding cell death induced to occur by autoschizis and not by apoptosis or other cell deaths. This report could provide more support for the usage of this vitamin combination named APATONE as inexpensive potent adjuvant or treatment in prostate cancers.

01 Aug 2012·Brazilian Journal of Medical and Biological ResearchQ4 · MEDICINE

2-Bromo-1,4-naphthoquinone: a potentially improved substitute of menadione in Apatone™ therapy

Q4 · MEDICINE

ArticleOA

Author: Graciani, F.S. ; Ximenes, V.F.

Apatone™, a combination of menadione (2-methyl-1,4-naphthoquinone, VK3) and ascorbic acid (vitamin C, VC) is a new strategy for cancer treatment. Part of its effect on tumor cells is related to the cellular pro-oxidative imbalance provoked by the generation of hydrogen peroxide (H2O2) through naphthoquinone redox cycling. In this study, we attempted to find new naphthoquinone derivatives that would increase the efficiency of H2O2 production, thereby potentially increasing its efficacy for cancer treatment. The presence of an electron-withdrawing group in the naphthoquinone moiety had a direct effect on the efficiency of H2O2 production. The compound 2-bromo-1,4-naphthoquinone (BrQ), in which the bromine atom substituted the methyl group in VK3, was approximately 10- and 19-fold more efficient than VK3 in terms of oxygen consumption and H2O2 production, respectively. The ratio [H2O2]produced / [naphthoquinone]consumed was 68 ± 11 and 5.8 ± 0.2 (µM/µM) for BrQ and VK3, respectively, indicating a higher efficacy of BrQ as a catalyst for the autoxidation of ascorbic acid. Both VK3 and BrQ reacted with glutathione (GSH), but BrQ was the more effective substrate. Part of GSH was incorporated into the naphthoquinone, producing a nucleophilic substitution product (Q-SG). The depletion of BrQ by GSH did not prevent its redox capacity since Q-SG was also able to catalyze the production of reactive oxygen species. VK3/VC has already been submitted to clinical trials for the treatment of prostate cancer and has demonstrated promising results. However, replacement of VK3 with BrQ will open new lines of investigation regarding this approach to cancer treatment.

100 Deals associated with Ascorbic Acid/Menadione

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Joint Diseases	Phase 2	-	Summa Health System (Ohio)	-
Prostatic Cancer	Phase 2	-	Ic Medtech Corp.	-
Prostatic Cancer	Phase 2	-	Summa Health System (Ohio)	-
Wounds and Injuries	Preclinical	United States	Summa Health System (Ohio)	-
Edema	Discovery	United States	Ic Medtech Corp.	01 Oct 2010
Foreign-Body Reaction	Discovery	United States	Ic Medtech Corp.	01 Oct 2010
Osteolysis	Discovery	United States	Ic Medtech Corp.	01 Oct 2010
Synovitis	Discovery	United States	Ic Medtech Corp.	01 Oct 2010
Polycystic Kidney Diseases	Discovery	United States	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01272830 (Apatone-B, CTgov)	Phase 2	Osteolysis \| Edema \| Synovitis \| Foreign-Body Reaction	57	Apatone®B (Oral Apatone®B)	woayfobeke(vpvpupyxip) = phzxjcmfqb wvkkiqiook (dhczcpocoz, jbinhwxuyt - ebsqujvkyk) View more	-	31 Jan 2018
				Placebo (Placebo)	woayfobeke(vpvpupyxip) = ywukxnrpkx wvkkiqiook (dhczcpocoz, tvwydyorjc - konjpohzne) View more