A Prospective Double-Blinded Clinical Trial Using Apatone®B for Care and Treatment of Proven Non-Infected Symptomatic Postoperative Total Joint Arthroplasties

This research study is being conducted to determine if taking oral (by mouth in pill form) Apatone®B (a combination of Vitamins C and K3) will reduce chronic joint discomfort and improve function of non-infected symptomatic postoperative total joint replacements.

Start Date01 Oct 2010

Sponsor / Collaborator

Ic Medtech Corp.

[+2]

100 Clinical Results associated with Ascorbic Acid/Menadione

100 Translational Medicine associated with Ascorbic Acid/Menadione

100 Patents (Medical) associated with Ascorbic Acid/Menadione

Literatures (Medical) associated with Ascorbic Acid/Menadione

02 Nov 2020·Oxidative Medicine and Cellular LongevityQ2 · BIOLOGY

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

Q2 · BIOLOGY

ArticleOA

Author: Ivanova, Donika ; Takeshima, Tsuguhide ; Higashi, Tatsuya ; Semkova, Severina ; Shibata, Sayaka ; Zhelev, Zhivko ; Lazarova, Dessislava ; Aoki, Ichio ; Bakalova, Rumiana ; Miller, Thomas

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 Jul 2010·Journal of Histochemistry & CytochemistryQ4 · BIOLOGY

Nucleolar Changes and Fibrillarin Redistribution Following Apatone Treatment of Human Bladder Carcinoma Cells

Q4 · BIOLOGY

Article

Author: Neal, Deborah ; McGuire, Karen ; Summers, Jack L. ; Thiry, Marc ; Perlaky, Laszlo ; Jamison, James M. ; Smetana, Karel ; Gilloteaux, Jacques

Ascorbate and menadione (Apatone) in a ratio of 100:1 kills tumor cells by autoschizis. In this study, vitamin-induced changes in nucleolar structure were evaluated as markers of autoschizis. Human bladder carcinoma (T24) cells were overlain with vitamins or with culture medium. Supernatants were removed at 1-hr intervals from 1 to 4 hr, and the cells were washed with PBS and prepared for assay. Apatone produced marked alterations in nucleolar structure including redistribution of nucleolar components, formation of ring-shaped nucleoli, condensation and increase of the proportion of perinucleolar chromatin, and the enlargement of nucleolar fibrillar centers. Immunogold labeling of the nucleolar rRNA revealed a granular localization in treated and sham-treated cells, and immunogold labeling of the rDNA revealed a shift from the fibrillar centers to the condensed perinucleolar chromatin. Fibrillarin staining shifted from the fibrillar centers and adjacent regions to a more homogeneous staining of the entire nucleolus and was consistent with the percentage of autoschizic cells detected by flow cytometry. Because autoschizis entails sequential reactivation of DNase I and DNase II, and because the fibrillarin redistribution following DNase I and Apatone treatment is identical, it appears that the nucleolar and fibrillarin changes are markers of autoschizis.

100 Deals associated with Ascorbic Acid/Menadione

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Joint Diseases	Phase 2	-	Ic Medtech Corp.	-
Joint Diseases	Phase 2	-	Summa Health System (Ohio)	-
Prostatic Cancer	Phase 2	-	Ic Medtech Corp.	-
Prostatic Cancer	Phase 2	-	Summa Health System (Ohio)	-
Edema	Preclinical	US	Summa Health System (Ohio)	01 Oct 2010
Edema	Preclinical	US	Ic Medtech Corp.	01 Oct 2010
Osteolysis	Preclinical	US	Ic Medtech Corp.	01 Oct 2010
Osteolysis	Preclinical	US	Summa Health System (Ohio)	01 Oct 2010
Synovitis	Preclinical	US	Summa Health System (Ohio)	01 Oct 2010
Synovitis	Preclinical	US	Ic Medtech Corp.	01 Oct 2010

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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)	huaeccbsds(evmzvwhcpg) = wxvrnqzspz gjfenbtxoo (zktddinwnj, sqrqrizhup - hdgkrghvja) View more	-	31 Jan 2018
				Placebo (Placebo)	huaeccbsds(evmzvwhcpg) = lfqnwlzvjo gjfenbtxoo (zktddinwnj, ycutrdoqge - ixjtoxxamk) View more

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