Didox is a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor. Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3). Furthermore, Didox increased expression of the antioxidant genes superoxide dismutase and catalase, and suppressed DCFH-DA fluorescence, indicating reduced reactive oxygen species production[3]. Didox was active against all human and murine AML (Acute Myeloid Leukemia) lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89-52.70 µM]). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. Didox was well tolerated and effective against preclinical models of AML[4]. Didox induced caspase-dependent multiple myeloma (MM) cell apoptosis[5]. Nuclear translocation of NF-κβ (p65) in response to LPS is inhibited by didox[6].
Didox 细胞实验
Cell Line
Concentration
Treated Time
Description
References
ARPE-19 epithelial cells
182 ± 23 µM (EC50)
14 days
To evaluate the anti-HCMV activity of Didox when used alone, the results showed an EC50 of 182 ± 23 µM in ARPE-19 cells.
Antiviral Res. 2013 Oct;100(1):151-8.
MRC-5 fibroblasts
82 ± 32 µM (EC50)
14 days
To evaluate the anti-HCMV activity of Didox when used alone, the results showed an EC50 of 82 ± 32 µM in MRC-5 cells.
Antiviral Res. 2013 Oct;100(1):151-8.
T-cells (B10.D2 and C57BL6 mice)
25 µM - 100 µM
24 - 48 hours
Didox significantly inhibited the secretion of cytokines IL-6, IFN-γ, TNF-α, IL-2, IL-13, IL-10 and IL-4.
J Inflamm (Lond). 2010 Aug 18;7:43.
Mouse embryonic fibroblast (MEF)
25 µM - 100 µM
24 - 96 hours
Didox significantly inhibited T-cell proliferation, with 25μM concentration reducing proliferation by approximately 90% at 96 hours post stimulation, and 50μM concentration completely blocking proliferation.
J Inflamm (Lond). 2010 Aug 18;7:43.
MDA-MB-468
30-600 µM
24 hours
Didox downregulates cyclin D1, cyclin A2, and cyclin E2, along with NF-κB signaling proteins p100, p105, and RelB, and increases Rb and pRb S807 expression.
Cancers (Basel). 2024 Feb 28;16(5):975.
MCF7
30-600 µM
24 hours
Didox downregulates an element of the cell cycle checkpoint, cyclin D1, accompanied by a reduction in NF-κB activity and induces cell cycle arrest at G1.
Cancers (Basel). 2024 Feb 28;16(5):975.
Mouse primary cardiomyocytes
1 µM
24 hours
To investigate the effect of DOX on RRM2 expression, results showed decreased RRM2 mRNA and protein levels
Biomolecules. 2022 Feb 12;12(2):299.
RAW264.7 macrophages
50 µM
24 hours
To evaluate the effects of Didox on LPS-induced inflammation and oxidative stress. Results showed that Didox significantly inhibited the mRNA expression of iNOS, IL-6, TNF-α, and COX-2, and reduced the secretion of NO, IL-6, and IL-10.
Chem Biol Interact. 2015 May 25;233:95-105.
HuH7 cells
1, 10, 25, 50, 100, 200 and 500 µM
24, 48 and 72 hours
Didox showed similar sensitivity in HuH7 cells with IC50 of 329.31 ± 31.55 µM at 48 h and 122.92 ± 13.21 µM at 72 h.
Pharmaceuticals (Basel). 2019 Sep 2;12(3):129.
HA22T/VGH cells
1, 10, 25, 50, 100, 200 and 500 µM
24, 48 and 72 hours
Didox reduced cell viability in a dose- and time-dependent manner with IC50 of 283.36 ± 18.82 µM at 48 h and 132.98 ± 7.97 µM at 72 h.
Pharmaceuticals (Basel). 2019 Sep 2;12(3):129.
SH-SY5Y
10 µM
3 hours
To evaluate the activation effect of Didox on HIF1 ODD-luc and Neh2-luc reporters. Results showed that Didox activated HIF1 ODD-luc reporter at concentrations above 100 µM but had no effect on Neh2-luc reporter.
Aging Dis. 2016 Dec 1;7(6):745-762.
MRC-5 fibroblasts
103 ± 19 µM (EC50)
5 days
To evaluate the anti-HCMV activity of Didox when used alone, the results showed an EC50 of 103 ± 19 µM in MRC-5 cells.
Antiviral Res. 2013 Oct;100(1):151-8.
Peritoneal mast cells
100 µM
6 hours
Didox significantly suppressed IL-33-induced IL-6 production
Cell Immunol. 2017 Sep;319:10-16.
Bone marrow derived mast cells (BMMC)
100 µM
6 hours
Didox significantly suppressed IL-33-induced production of IL-6, IL-13, TNF, and MIP-1α
Cell Immunol. 2017 Sep;319:10-16.
Peritoneal mast cells
100 µM
6 hours
Didox suppressed IgE-mediated IL-6 and IL-13 secretion but had no significant effect on MCP-1.
Cell Immunol. 2017 Dec;322:41-48.
Mouse bone marrow-derived mast cells (BMMC)
100 µM
6 hours
Didox suppressed IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF, and MIP-1a.
Cell Immunol. 2017 Dec;322:41-48.
HT-29
501.6 ± 53 µM (IC50)
72 hours
To evaluate the cytotoxic effect of Didox on HT-29 cells, results showed an IC50 of 501.6 ± 53 μM for Didox alone.
Sci Rep. 2016 Nov 14;6:36855.
HCT 116
105 ± 1.5 µM (IC50)
72 hours
To evaluate the cytotoxic effect of Didox on HCT 116 cells, results showed an IC50 of 105 ± 1.5 μM for Didox alone.
Sci Rep. 2016 Nov 14;6:36855.
MCF-7 cells
9.506 ± 0.08 μg/ml (IC50)
72 hours
Evaluate the effect of Didox on Herceptin cytotoxicity, results showed that Didox combined with Herceptin significantly reduced the IC50 value, indicating synergistic effect
Sci Rep. 2015 Jul 9;5:12054.
T47D cells
82.975 ± 5.95 μg/ml (IC50)
72 hours
Evaluate the effect of Didox on Herceptin cytotoxicity, results showed that Didox combined with Herceptin significantly reduced the IC50 value, indicating synergistic effect
Sci Rep. 2015 Jul 9;5:12054.
H9C2 cells
60 µM
To investigate the effect of RRM2 on cell proliferation, results showed RRM2 overexpression reduced adverse effects of DOX on proliferation
Biomolecules. 2022 Feb 12;12(2):299.
Didox 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57/B6 mice
DOX-induced cardiomyopathy model
Intraperitoneal injection
15 mg/kg
5 days
To investigate the role of RRM2 in DOX-induced cardiomyopathy, results showed RRM2 overexpression alleviated myocardial injury
Biomolecules. 2022 Feb 12;12(2):299.
Mice (C57BL6 and B10.D2)
Mixed lymphocyte reaction (MLR) model
In vitro culture
25 μM - 100 μM
Single treatment, lasting 6 days
Didox significantly inhibited T-cell proliferation and cytokine secretion in MLR, with 100μM dose inhibiting IFN-γ and IL-2 production to levels comparable to normal controls.
J Inflamm (Lond). 2010 Aug 18;7:43.
Mice
LPS-induced neuroinflammation model
Intraperitoneal injection
250 mg/kg
Starting 24 h post-LPS injection and continued for 6 days
Didox treatment reversed AIS disruption and accelerated AIS recovery.
J Neuroinflammation. 2017 Jun 8;14(1):116
C57BL/6J mice
IgE-mediated passive systemic anaphylaxis model
Intraperitoneal (IP) injection
350 mg/kg
Single dose, 6 hours before anaphylaxis induction
Didox significantly attenuated the temperature drop in IgE-mediated passive systemic anaphylaxis.
Cell Immunol. 2017 Dec;322:41-48.
Nude mice
MCF7 PR breast cancer model
Intraperitoneal injection
425 mg/kg/day
Once daily for 9 days
Didox alone or in combination with palbociclib significantly inhibited the growth of ER+ palbociclib-resistant tumors.
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