didox (NSC-324360) / Molecules for Health - LARVOL DELTA

Didox, a ribonucleotide reductase inhibitor with iron chelator properties, counteracts the in vitro and in vivo growth of rhabdomyosarcoma cells. (PubMed, Biochem Pharmacol) - "Finally, the combination of sublethal doses of Actinomycin-D and didox is effective in decreasing cell viability and clonogenicity of RMS cells. Therefore, our data suggests the effectiveness of the RR inhibitor didox on both in vitro and in vivo RMS proliferation."

Journal • Preclinical • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ANXA5 • RRM1 • RRM2 • RRM2B • TFRC

Is Adjuvant Chemotherapy Needed in Small Node-Negative Triple Negative Breast Cancer? (SABCS 2024) - "Other chemotherapeutic regimens include CMF and Didox...Subgroup analysis according to tumor size (T1a, T1b), TIL (≤ 30%, >30%), and chemotherapeutic regimens (only adriamycin and/or taxane) also showed that adjuvant chemotherapy had no significant impact on recurrence... In the overall small node-negative TNBC patient population, adjuvant chemotherapy did not significantly impact recurrence. Avoidance of chemotherapy in T1a/bN0 TNBC patients can be considered. Further clinical studies are needed to evaluate the efficacy of adjuvant chemotherapy in patients with small node-negative TNBC."

Clinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers. (PubMed, Cancers (Basel)) - "Here, we report that didox, an inhibitor of ribonucleotide reductase in combination with palbociclib, can overcome palbociclib resistance in ER-positive and ER-negative breast cancers. Our current study also reports that the CCND1 and RRM2 upregulation associated with palbociclib-resistant breast cancers decreases upon ribonucleotide reductase inhibition. Our data present a novel and promising biomarker-driven combination therapeutic approach for the treatment of ER-positive and ER-negative breast cancers that involves the inhibition of the CDK4/6-cyclinD1/pRb cell cycle axis that merits further clinical investigation in human models."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • ER • RRM2

Hepatitis C Virus Down-Regulates the Expression of Ribonucleotide Reductases to Promote Its Replication. (PubMed, Pathogens) - "Moreover, inhibitors to RRMs, including Didox, Trimidox and hydroxyurea, enhance HCV replication. Among various HCV viral proteins, the NS5A and/or NS3/4A proteins suppress the expression of RRMs. When these are taken together, the results suggest that HCV down-regulates the expression of RRMs in cultured cells to promote its replication."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Multiple Sclerosis • RRM1 • RRM2

Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells. (PubMed, J Cancer Res Clin Oncol) - "Our study reveals that combined targeting of ATR and RNR was effective against Ewing's sarcoma in vitro and thus rationalises an in vivo exploration into the potential of combining ATR and RNR inhibitors as a new strategy for the treatment of this challenging disease."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • BBC3 • CASP3 • CASP7 • CDKN1A • TP53

Targeting RRM2 & cell cycle for breast cancer treatment (AACR 2023) - "Previously, we have shown that didox (DDX) can significantly halt malignant breast cancer cell division in combination with the anthracycline drug doxorubicin by targeting RRM2, mutant p53 and NFkB regulatory proteins. Additionally, we observed that didox alone or in combination with palbociclib alters the cell cycle of MCF7 and MDA-MB-468 parental and palbociclib resistant breast cancer cells. Our data presents a novel and promising approach for the treatment of ER positive and ER negative breast cancer that involves inhibition of RRM2 and cell cycle that merits further clinical investigation in animal and human models."

Breast Cancer • Eye Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Retinoblastoma • Solid Tumor • Triple Negative Breast Cancer • CCND1 • ER • HER-2 • RRM1 • RRM2 • TP53

Targeting RRM2 for the treatment of palbociclib resistant breast cancer (SABCS 2022) - "In our previous study, we have shown that RRM2 is upregulated in ER positive tamoxifen resistant BC. Previously, we have also reported that didox (DDX) which is a unique RRM2 enzyme inhibitor can significantly halt malignant breast cancer cell division in combination with an anthracycline drug doxorubicin by targeting RRM2, mutant p53 and NFkB regulatory proteins...Cell proliferation studies confirm the synergistic combinatorial effect of palbociclib and DDX compared to palbociclib or DDX alone. We also report that DDX alone or in combination with palbociclib downregulates cell cycle and NFkB proteins in palbociclib resistant ER positive MCF7 and ER negative MBA-MB-468 breast cancer cell lines."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • RRM1 • RRM2 • TP53

RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway. (PubMed, Biomolecules) - "Consistently, DIDOX, an inhibitor of RRM2, attenuated the protective effect of RRM2. Mechanistically, we found that AKT/mTOR inhibitors could reverse the function of RRM2 overexpression on DOX-induced autophagy and apoptosis, which means that RRM2 could have regulated DOX-induced cardiotoxicity through the AKT/mTOR signaling pathway. In conclusion, our experiment established that RRM2 could be a potential treatment in reversing DOX-induced cardiac dysfunction."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology • BECN1 • CASP3 • RRM2

[VIRTUAL] RRM2 and mutant p53 as therapeutic targets in TNBC (AACR 2021) - "As such, dose-dense chemotherapeutic agents used in combination, such as doxorubicin (DOXO) with cyclophosphamide, is the regimen of choice for TNBC...Didox (3,4 dihydroxybenzohydroxamic acid) is a unique RR inhibitor with iron chelating and free radical scavenging properties...Finally, we have identified that RRM2 protein levels increase in TNBC with progression of stage as measured in patient tissue microarray analysis. Our data presents a novel and promising approach for the treatment of TNBC that involves inhibition of RRM2, NF-kB activation, and mutant p53 that merits further clinical investigation in human models."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR • RRM2 • TP53

Molecular Targeting of RRM2, NF-κB, and Mutant TP53 for the Treatment of Triple-Negative Breast Cancer. (PubMed, Mol Cancer Ther) - "Additionally, the use of Didox was also found to ameliorate the toxic myocardial effects of doxorubicin in vivo as measured by heart mass, left ventricular diameter, and serum troponin T levels. The data present a novel and promising approach for the treatment of TNBC that merits further clinical evaluation in humans."

Journal • Breast Cancer • Cardiovascular • Congestive Heart Failure • Estrogen Receptor Positive Breast Cancer • Heart Failure • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • RRM2 • TP53

Utility of the optical quality analysis system for decision-making in Nd: YAG laser posterior capsulotomy in patients with light posterior capsule opacity. (PubMed, BMC Ophthalmol) - "The OSI was useful for evaluating of PCO and prediction of beneficial capsulotomy. Especially for patients with slight PCO and better visual acuity, OSI is more valuable than CDVA and completely objective examination."

Clinical • Journal • Cataract

Quality of life of patients after phacoemulsification with implantation of trifocal intraocular lens (PubMed, Vestn Oftalmol) - "Trifocal intraocular lenses ensure higher quality of life for patients after phacoemulsification when compared with monofocal lenses. Dysphotopsias have some effect on the QoL of patients with multifocal correction, but 82% of them are highly satisfied with the surgery outcome."

Clinical • HEOR • Journal • Cataract • Ophthalmology

The Association between Socioeconomic Factors and Visual Function among Patients with Age-Related Cataracts. (PubMed, J Ophthalmol) - "Data on the best-corrected visual acuity (BCVA), Lens Opacities Classification System III (LOCS III) score, Visual Function Index-14 (VF-14) score, total and subscale scores of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), per capita disposable income (PCDI), medical resource-related indicators, and investments in the energy industry were obtained...Patients in higher economic regions with greater medical resources show a greater demand to undergo cataract surgery at a better subjective and objective visual function. The energy industry has a significant effect on cataracts, especially the posterior subcapsular cataract, and thus more attention should be paid to people in regions with abundant energy industries."

Clinical • Journal • Cataract • Ophthalmology

Evaluation of retinal light scattering, visual acuity, refraction and subjective satisfaction in patients after Acrysof IQ PanOptix intraocular lens implantation. (PubMed, Cesk Slov Oftalmol) - "Subjective satisfaction was assessed using a standardized VF-14 questionnaire at least 1 year after surgery (mean follow-up of 27 months)...In only 6 eyes of 4 patients, the resulting value was outside the physiological range used for eyes with lens crystallina The value of light scattering on the retina is a factor affecting the degree of sensitivity to glare after implantation of multifocal intraocular lenses. In our group, we observed a deviation from the physiological range of retinal light scattering in only 6 eyes of 4 patients, but this did not lead to a deterioration in subjective postoperative satisfaction."

Clinical • Journal • Cataract • Ophthalmology

A comparative evaluation of diffractive trifocal and new refractive/extended depth of focus intraocular lenses for refractive lens exchange. (PubMed, Curr Eye Res) - "The refractive results and visual outcomes at all distances of EDOF and trifocal IOLs were highly satisfactory. However, the EDOF design in the Lucidis IOL achieves lower rates of glare in the early period after refractive lens exchange."

Journal • Ophthalmology

Validation and comparison of the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) and the Visual Function Index-14 (VF-14) in patients with cataracts: a multicentre study. (PubMed, Acta Ophthalmol) - "Neither the NEI VFQ-25 nor VF-14 is optimal for the assessment of vision-related quality of life in typical Chinese patients with cataracts. The potential deficiencies of the questionnaires should be taken into consideration prior to application of the instruments or interpretation of the results."

Clinical • Journal • Cataract • Ophthalmology

Didox (3,4-dihydroxybenzohydroxamic acid) reduces the vascular inflammation induced by acute intravascular hemolysis. (PubMed, Blood Cells Mol Dis) - No abstract available

Journal • Hematological Disorders • Immunology

Targeting ribonucleotide reductase M2 using didox causes inhibition of estrogen receptor-negative, inflammatory breast cancer cell proliferation and tumor emboli formation in culture (AACR 2018) - "ER- inflammatory breast cancer (IBC) cell lines SUM149 (ER-, PR-, EGFR-activated), lapatinib-resistant SUM149 (rSUM149), and non-IBC BT474M1 metastatic subline of BT474 (ER+, PR+, HER2+) were compared for the cytotoxic and cytostatic effects of didox using cell viability (trypan blue exclusion) and proliferation (MTT) assays. Further, there is a need to identify new therapies that can inhibit IBC tumor emboli formation and migration. Didox has demonstrated minimal toxicity in human phase I/II cancer clinical trials and therefore is an attractive strategy for inflammatory breast cancer therapy.Support in part from the Development funds (GRD) of the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236 and Department of Defense Breakthrough Level 2 W81XWH-17-1-0297 (GRD)."

Preclinical • HER2 Breast Cancer • Hormone Receptor Breast Cancer

The cytotoxicity of gallium maltolate in glioblastoma cells is enhanced by metformin through combined action on mitochondrial complex 1. (PubMed, Oncotarget) - "Metformin did not affect GaM action on cellular iron uptake or transferrin receptor1 expression nor did it enhance the cytotoxicity of the RR inhibitor Didox. Our results show that GaM inhibits complex I by disrupting iron-sulfur cluster assembly and that its cytotoxicity can be synergistically enhanced by metformin through combined action on complex I."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells. (PubMed, Pharmaceuticals (Basel)) - "...Didox, a derivative of hydroxyurea (HU), is one of the most potent pharmaceutical inhibitors of this enzyme, with low in vivo side effects...Interestingly, cell treatments with didox caused changes of cellular iron content, TfR1 and ferritin levels comparable to those caused by the iron chelators, deferoxamine (DFO) and deferiprone (DFP)...Structural modeling indicated that didox is a bidentated iron chelator with two theoretical possible positions for the binding and among them that with the two hydroxyls of the catechol group acting as ligands is the more likely one. The iron chelating property of didox may contribute to its antitumor activity not only blocking the formation of the tyrosil radical on Tyr122 (such as HU) on RRM2 (essential for its activity) but also sequestering the iron needed by this enzyme and to the cell proliferation."

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Potential tumor‑suppressive role of microRNA‑99a‑3p in sunitinib‑resistant renal cell carcinoma cells through the regulation of RRM2. (PubMed, Int J Oncol) - "Furthermore, the RRM2 inhibitor Didox (3,4‑dihydroxybenzohydroxamic acid) exhibited anticancer effects in the SU‑R‑786‑o cells and other RCC cells. To the best of our knowledge, this is the first report demonstrating that miR‑99a‑3p directly regulates RRM2. Identifying novel genes targeted by tumor‑suppressive miR‑99a‑3p in sunitinib‑resistant RCC cells may improve our understanding of intrinsic or acquired resistance and facilitate the development of novel therapeutic strategies."

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