A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.
Journal
Drugs
ISSN: 1179-1950
Titre abrégé: Drugs
Pays: New Zealand
ID NLM: 7600076
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
accepted:
22
01
2023
medline:
29
3
2023
pubmed:
16
3
2023
entrez:
15
3
2023
Statut:
ppublish
Résumé
Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.
Identifiants
pubmed: 36920652
doi: 10.1007/s40265-023-01838-z
pii: 10.1007/s40265-023-01838-z
pmc: PMC10015535
doi:
Substances chimiques
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
RRx-001
0
Nucleotides
0
Banques de données
ClinicalTrials.gov
['NCT03699956']
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
389-402Informations de copyright
© 2023. The Author(s).
Références
Duff M. Theory of everything: the big questions in physics. New Scientist. 2011;210(2815):ii–iii.
doi: 10.1016/S0262-4079(11)61274-8
Hutter M. A complete theory of everything (will be subjective). Algorithms. 2010;3(4):329–50.
doi: 10.3390/a3040329
Christgen S, Kanneganti TD. Inflammasomes and the fine line between defense and disease. Curr Opin Immunol. 2020;62:39–44.
pubmed: 31837596
doi: 10.1016/j.coi.2019.11.007
Lieberman J, Wu H, Kagan JC. Gasdermin D activity in inflammation and host defense. Sci Immunol. 2019;4(39).
Heidland A, Klassen A, Rutkowski P, Bahner U. The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance? J Nephrol. 2006;19(Suppl 10):S102–9.
pubmed: 16874721
Eigenbrod T, Dalpke AH. Bacterial RNA: an underestimated stimulus for innate immune responses. J Immunol. 2015;195(2):411–8.
pubmed: 26138638
doi: 10.4049/jimmunol.1500530
Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10(3):241–7.
pubmed: 19221555
pmcid: 2820724
doi: 10.1038/ni.1703
Kayagaki N, Warming S, Lamkanfi M, Walle LV, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479(7371):117–21.
pubmed: 22002608
doi: 10.1038/nature10558
Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Regulation of the NLRP3 inflammasome by post-translational modifications and small molecules. Front Immunol. 2020;11: 618231.
pubmed: 33603747
doi: 10.3389/fimmu.2020.618231
Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. 2014;1319(1):82–95.
pubmed: 24840700
pmcid: 4074217
doi: 10.1111/nyas.12458
Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–89.
pubmed: 31036962
pmcid: 7807242
doi: 10.1038/s41577-019-0165-0
Malik A, Kanneganti T-D. Inflammasome activation and assembly at a glance. J Cell Sci. 2017;130(23):3955–63.
pubmed: 29196474
pmcid: 5769591
doi: 10.1242/jcs.207365
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10(2):417–26.
pubmed: 12191486
doi: 10.1016/S1097-2765(02)00599-3
Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25(5):713–24.
pubmed: 17349957
doi: 10.1016/j.molcel.2007.01.032
Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–71.
pubmed: 26375259
doi: 10.1038/nature15541
Torti SV, Torti FM. Ironing out cancer. Cancer Res. 2011;71(5):1511–4.
pubmed: 21363917
pmcid: 3079335
doi: 10.1158/0008-5472.CAN-10-3614
Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35(3):515–27.
pubmed: 24343361
doi: 10.1093/carcin/bgt480
D’Errico G, Machado HL, Sainz B Jr. A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clin Transl Med. 2017;6(1):3.
pubmed: 28050779
pmcid: 5209322
Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med. 2019;47(5):632–42.
pubmed: 30747773
pmcid: 7254685
doi: 10.1097/CCM.0000000000003685
Qian W, Ye Y, Zuo L, Song T, Xu Q, Wang Y, et al. Immune checkpoint inhibitors use and effects on prognosis of COVID-19 infection: a systematic review and meta-analysis. Immunotherapy. 2021;13(15):1271–82.
pubmed: 34431319
doi: 10.2217/imt-2021-0007
Afrasiabi K, Zhou YH, Fleischman A. Chronic inflammation: is it the driver or is it paving the road for malignant transformation? Genes Cancer. 2015;6(5–6):214–9.
pubmed: 26124920
pmcid: 4482242
doi: 10.18632/genesandcancer.64
Nedeva C, Menassa J, Puthalakath H. Sepsis: inflammation is a necessary evil. Front Cell Dev Biol. 2019;7:108.
pubmed: 31281814
pmcid: 6596337
doi: 10.3389/fcell.2019.00108
Pahwa R, Goyal A, Jialal I. Chronic Inflammation. StatPearls. Treasure Island (FL): StatPearls Publishing, Copyright © 2022, StatPearls Publishing LLC.; 2022.
Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11(1):316–29.
pubmed: 33391477
pmcid: 7681075
doi: 10.7150/thno.49713
Cicchese JM, Evans S, Hult C, Joslyn LR, Wessler T, Millar JA, et al. Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology. Immunol Rev. 2018;285(1):147–67.
pubmed: 30129209
pmcid: 6292442
doi: 10.1111/imr.12671
Ringel-Scaia VM, McDaniel DK, Allen IC. The goldilocks conundrum: NLR inflammasome modulation of gastrointestinal inflammation during inflammatory bowel disease. Crit Rev Immunol. 2016;36(4):283–314.
pubmed: 28322135
pmcid: 5364818
doi: 10.1615/CritRevImmunol.2017019158
Blevins HM, Xu Y, Biby S, Zhang S. The NLRP3 inflammasome pathway: a review of mechanisms and inhibitors for the treatment of inflammatory diseases. Front Aging Neurosci. 2022;14: 879021.
pubmed: 35754962
pmcid: 9226403
doi: 10.3389/fnagi.2022.879021
Coll RC, Schroder K, Pelegrín P. NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol Sci. 2022;43(8):653–68.
pubmed: 35513901
doi: 10.1016/j.tips.2022.04.003
Lu Y, Xiao G, Luo W. Minocycline Suppresses NLRP3 Inflammasome Activation in Experimental Ischemic Stroke. Neuroimmunomodulation. 2016;23(4):230-8.
Wang HM, Zhang T, Huang JK, Xiang JY, Chen JJ, Fu JL, et al. Edaravone Attenuates the Proinflammatory Response in Amyloid-β-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion. Cell Physiol Biochem. 2017;43(3):1113-25.
Feng L, Chen Y, Ding R, Fu Z, Yang S, Deng X, et al. P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation. 2015;12:190
Ismael S, Nasoohi S, Ishrat T. MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury. J Neurotrauma. 2018;35(11):1294-303
Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 2019;15(6):556–9.
pubmed: 31086327
doi: 10.1038/s41589-019-0277-7
Sánchez-Fernández A, Skouras DB, Dinarello CA, López-Vales R. OLT1177 (Dapansutrile), a selective NLRP3 inflammasome inhibitor, ameliorates experimental autoimmune encephalomyelitis pathogenesis. Front Immunol. 2019;10:2578.
pubmed: 31736980
pmcid: 6839275
doi: 10.3389/fimmu.2019.02578
Coll RC, Robertson AAB, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–55.
pubmed: 25686105
pmcid: 4392179
doi: 10.1038/nm.3806
Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A. 2018;115(7):E1530–9.
pubmed: 29378952
pmcid: 5816172
doi: 10.1073/pnas.1716095115
Oronsky B, Scicinski J, Ning S, Peehl D, Oronsky A, Cabrales P, et al. Rockets, radiosensitizers, and RRx-001: an origin story part I. Discov Med. 2016;21(115):173–80.
pubmed: 27115167
Oronsky B, Abrouk N, Caroen S, Lybeck M, Guo X, Wang X, et al. A 2022 update on extensive stage small-cell lung cancer (SCLC). J Cancer. 2022;13(9):2945–53.
pubmed: 35912017
pmcid: 9330463
doi: 10.7150/jca.75622
Morgensztern D, Rose M, Waqar SN, Morris J, Ma PC, Reid T, et al. RRx-001 followed by platinum plus etoposide in patients with previously treated small-cell lung cancer. Br J Cancer. 2019;121(3):211–7.
pubmed: 31231122
pmcid: 6738071
doi: 10.1038/s41416-019-0504-8
Caroen S, Oronsky B, Reid T, Pandher K, Lopez A. Superficial venous-associated inflammation from direct IV administration of RRx-001 in rats. Int J Med Sci. 2022;19(11):1628–30.
pubmed: 36237984
pmcid: 9553854
doi: 10.7150/ijms.76615
Oronsky B, Paulmurugan R, Foygel K, Scicinski J, Knox SJ, Peehl D, et al. RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials. Expert Opin Investig Drugs. 2017;26(1):109–19.
pubmed: 27935336
doi: 10.1080/13543784.2017.1268600
Oronsky B, Cabrales P, Caroen S, Guo X, Scribner C, Oronsky A, et al. RRx-001, a downregulator of the CD47- SIRPα checkpoint pathway, does not cause anemia or thrombocytopenia. Expert Opin Drug Metab Toxicol. 2021;17(4):355–7.
pubmed: 33432831
doi: 10.1080/17425255.2021.1876025
Oronsky B, Reid T, Cabrales P. Vascular priming with RRx-001 to increase the uptake and accumulation of temozolomide and irinotecan in orthotopically implanted gliomas. J Drug Target. 2021;29(9):998–1003.
pubmed: 34016002
doi: 10.1080/1061186X.2021.1904248
Zhao H, Ning S, Scicinski J, Oronsky B, Knox SJ, Peehl DM. Epigenetic effects of RRx-001: a possible unifying mechanism of anticancer activity. Oncotarget. 2015;6(41):43172–81.
pubmed: 26657731
pmcid: 4791224
doi: 10.18632/oncotarget.6526
Snoy PJ. Establishing efficacy of human products using animals: the us food and drug administration’s “animal rule.” Vet Pathol. 2010;47(5):774–8.
pubmed: 20551476
doi: 10.1177/0300985810372506
Raghunand N, Scicinski J, Guntle GP, Jagadish B, Mash EA, Bruckheimer E, et al. Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. Oncotarget. 2017;8(60):102511–20.
pubmed: 29254266
pmcid: 5731976
doi: 10.18632/oncotarget.18455
Lin H, Yang M, Li C, Lin B, Deng X, He H, et al. An RRx-001 analogue with potent anti-NLRP3 inflammasome activity but without high-energy nitro functional groups. Front Pharmacol. 2022;13: 822833.
pubmed: 35250572
pmcid: 8892206
doi: 10.3389/fphar.2022.822833
Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Mol Aspects Med. 2020;76: 100924.
pubmed: 33187725
doi: 10.1016/j.mam.2020.100924
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–20.
pubmed: 27291964
doi: 10.1038/nri.2016.58
Chen Y, He H, Lin B, Chen Y, Deng X, Jiang W, et al. RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor. Cell Mol Immunol. 2021;18(6):1425–36.
pubmed: 33972740
pmcid: 8166941
doi: 10.1038/s41423-021-00683-y
Fang J, She J, Lin F, Wu J-C, Han R, Sheng R, et al. RRx-001 exerts neuroprotection against LPS-induced microglia activation and neuroinflammation through disturbing the TLR4 pathway. Front Pharmacol. 2022;13:2.
Foygel K, Sekar TV, Paulmurugan R. Monitoring the antioxidant mediated chemosensitization and are-signaling in triple negative breast cancer therapy. PLoS ONE. 2015;10(11): e0141913.
pubmed: 26536456
pmcid: 4633093
doi: 10.1371/journal.pone.0141913
Kopacz A, Kloska D, Forman HJ, Jozkowicz A, Grochot-Przeczek A. Beyond repression of Nrf2: an update on Keap1. Free Radic Biol Med. 2020;157:63–74.
pubmed: 32234331
pmcid: 7732858
doi: 10.1016/j.freeradbiomed.2020.03.023
Oronsky B, Reid TR, Oronsky A, Caroen S, Carter CA, Cabrales P. Brief report: RRx-001 is a c-Myc inhibitor that targets cancer stem cells. Oncotarget. 2018;9(34):23439–42.
pubmed: 29805745
pmcid: 5955127
doi: 10.18632/oncotarget.25211
Ning S, Sekar TV, Scicinski J, Oronsky B, Peehl DM, Knox SJ, et al. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001. Oncotarget. 2015;6(25):21547–56.
pubmed: 26280276
pmcid: 4673285
doi: 10.18632/oncotarget.4249
Oronsky B, Caroen S, Abrouk N, Reid TR. RRx-001 and the “Right stuff”: protection and treatment in outer space. Life Sci Sp Res. 2022;35:69–75.
Rébé C, Ghiringhelli F. Interleukin-1β and Cancer. Cancers (Basel). 2020;12(7).
Tomita Y, Oronsky B, Abrouk N, Cabrales P, Reid TR, Lee MJ, et al. In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit. Transl Lung Cancer Res. 2021;10(1):274–8.
pubmed: 33569311
pmcid: 7867783
doi: 10.21037/tlcr-20-359
Theivanthiran B, Evans KS, DeVito NC, Plebanek M, Sturdivant M, Wachsmuth LP, et al. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest. 2020;130(5):2570–86.
pubmed: 32017708
pmcid: 7190922
doi: 10.1172/JCI133055
Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol. 2003;13(1):62–72.
pubmed: 12520465
doi: 10.1053/srao.2003.50006
Oronsky B, Goyal S, Kim MM, Cabrales P, Lybeck M, Caroen S, et al. A review of clinical radioprotection and chemoprotection for oral mucositis. Transl Oncol. 2018;11(3):771–8.
pubmed: 29698934
pmcid: 5918142
doi: 10.1016/j.tranon.2018.03.014
Oronsky B, Reid TR, Larson C, Carter CA, Brzezniak CE, Oronsky A, et al. RRx-001 protects against cisplatin-induced toxicities. J Cancer Res Clin Oncol. 2017;143(9):1671–7.
pubmed: 28417195
doi: 10.1007/s00432-017-2416-4
Scicinski J, Oronsky B, Ning S, Knox S, Peehl D, Kim MM, et al. NO to cancer: The complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001. Redox biology. 2015;6:1-8.
Ning S, Bednarski M, Oronsky B, Scicinski J, Saul G, Knox SJ. Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials. Cancer research. 2012;72(10):2600-8.
Jurgensen KJ, Skinner WKJ, Oronsky B, Abrouk ND, Graff AE, Landes RD, et al. RRx-001 Radioprotection: Enhancement of Survival and Hematopoietic Recovery in Gamma-Irradiated Mice. Front Pharmacol. 2021;12:676396.
Kim EJH, Carter CA, Reid TR, Caroen S, Oronsky B, Abrouk ND, et al. Phase I study (PAYLOAD) of RRx-001 + irinotecan in patients with advanced solid malignancies. J Clin Oncol. 2020;38(15): e16031.
doi: 10.1200/JCO.2020.38.15_suppl.e16031
Oronsky B, Ao-Ieong ESY, Yalcin O, Carter CA, Cabrales P. Cardioprotective effect of phase 3 clinical anticancer agent, RRx-001, in doxorubicin-induced acute cardiotoxicity in mice. Mol Pharm. 2019;16(7):2929–34.
pubmed: 31038318
doi: 10.1021/acs.molpharmaceut.9b00150
Cabrales P CS, Reid TR, Oronsky B NO fatigue: RRx-001, a nitric oxide donor under hypoxia, improves endurance and skeletal muscle oxidative capacity. Nitric Oxide Journal (In Press). 2022
Cabrales P, Caroen S, Oronsky A, Carter C, Trepel J, Summers T, et al. The macrophage stimulating anti-cancer agent, RRx-001, protects against ischemia-reperfusion injury. Expert Rev Hematol. 2017;10(6):575–82.
pubmed: 28448172
pmcid: 8051333
doi: 10.1080/17474086.2017.1324779
Brouse C, Ortiz D, Su Y, Oronsky B, Scicinski J, Cabrales P. Impact of hemoglobin nitrite to nitric oxide reductase on blood transfusion for resuscitation from hemorrhagic shock. Asian J Transfus Sci. 2015;9(1):55–60.
pubmed: 25722574
pmcid: 4339933
doi: 10.4103/0973-6247.150952
Yalcin O, Oronsky B, Carvalho LJM, Kuypers FA, Scicinski J, Cabrales P. From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria. Malar J. 2015;14(1):218.
pubmed: 26017006
pmcid: 4453052
doi: 10.1186/s12936-015-0720-5
Ma M, Li G, Qi M, Jiang W, Zhou R. Inhibition of the inflammasome activity of NLRP3 attenuates HDM-induced allergic asthma. Front Immunol. 2021;12:2.
doi: 10.3389/fimmu.2021.718779
Reid T CS, Oronsky B, editor Phase 3 Anticancer Agent, RRx-001, Ameliorates Hypoxia-induced Pulmonary Hypertension. American Heart Association'; 2022; San Diego, California.
Reid T OB, Caroen S, Cabrales P editor The direct NLRP3 inhibitor and Phase 3 small molecule anticancer agent, RRx-001, protects aged triple transgenic Alzheimer's disease model mice from CNS degeneration and cognitive decline. Alzheimer's Association International Conference (AAIC) - 2022; 2022; San Diego2022.
Xu Q, Zhou X, Strober W, Mao L. Inflammasome regulation: therapeutic potential for inflammatory bowel disease. Molecules. 2021;26(6):2.
doi: 10.3390/molecules26061725
Alehashemi S, Goldbach-Mansky R. Human autoinflammatory diseases mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-inflammasome dysregulation updates on diagnosis, treatment, and the respective roles of IL-1 and IL-18. Front Immunol. 2020;11:2.
doi: 10.3389/fimmu.2020.01840
Park JJH, Siden E, Zoratti MJ, Dron L, Harari O, Singer J, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572.
pubmed: 31533793
pmcid: 6751792
doi: 10.1186/s13063-019-3664-1
Huang Z, Fu J, Zhang Y. Nitric oxide donor-based cancer therapy: advances and prospects. J Med Chem. 2017;60(18):7617–35.
pubmed: 28505442
doi: 10.1021/acs.jmedchem.6b01672
Scicinski J, Fisher G, Carter C, Cho-Phan C, Kunz P, Ning S, et al. The development of RRx-001, a novel nitric-oxide-mediated epigenetically active anticancer agent. Redox Biol. 2015;5:422.
pubmed: 28162292
doi: 10.1016/j.redox.2015.09.035
Peters S, Julien S, Heiduschka P, Grisanti S, Ziemssen F, Adler M, et al. Antipermeability and antiproliferative effects of standard and frozen bevacizumab on choroidal endothelial cells. Br J Ophthalmol. 2007;91(6):827–31.
pubmed: 17179166
doi: 10.1136/bjo.2006.109702
Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331–5.
pubmed: 16156152
doi: 10.3928/1542-8877-20050701-14
Carroll J. One drug, many uses. Biotechnol Healthc. 2005;2(5):56–61.
pubmed: 23424312
pmcid: 3570995
Jurgensen KJ, Skinner WKJ, Oronsky B, Abrouk ND, Graff AE, Landes RD, et al. RRx-001 radioprotection: enhancement of survival and hematopoietic recovery in gamma-irradiated mice. Front Pharmacol. 2021;12: 676396.
pubmed: 33967816
pmcid: 8100686
doi: 10.3389/fphar.2021.676396
Das DS, Ray A, Das A, Song Y, Tian Z, Oronsky B, et al. A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia. 2016;30(11):2187–97.
pubmed: 27118403
pmcid: 5093055
doi: 10.1038/leu.2016.96
Bonomi MR, Blakaj D, Sher D, Kabarriti R, Colvett K, Reiner S, et al. Phase 2 pilot trial of RRx-001 as an anti-mucositis agent in patients with head and neck cancer treated with chemoradiation (PREVLAR). J Clin Oncol. 2022;40(16):6078.
doi: 10.1200/JCO.2022.40.16_suppl.6078
Oronsky B, Scicinski J, Ning S, Peehl D, Oronsky A, Cabrales P, et al. RRx-001, A novel dinitroazetidine radiosensitizer. Invest New Drugs. 2016;34(3):371–7.
pubmed: 26841903
pmcid: 4859863
doi: 10.1007/s10637-016-0326-y
U.S. Armed Forces Radiobiology Research Institute (AFRRI) 2017.
Oronsky B, Scicinski J, Cabrales P. Abstract 12627: clinical anticancer agent, RRx-001, protects from doxorubicin-induced cardiotoxicity. Circulation. 2016;134(1):12627.
Caroen SRT, Oronsky B, Cabrales P. The NLRP3 inhibitor and Nrf2 agonist, RRx-001, ameliorates non-alcoholic fatty liver disease (NAFLD/NASH) in rats. J Clin Lipidol. 2022;16:3.
doi: 10.1016/j.jacl.2022.05.053
Scicinski J, Oronsky B, Caroen S, Cabrales P, Summers TA, Reid TR, et al. Chapter 3 - RRx-001 Reset: Chemoresensitization via NO-Mediated M1 Macrophage Repolarization. In: Bonavida B, editor. Nitric Oxide (Donor/Induced) in Chemosensitizing. 1: Academic Press; 2017. p. 35-56.
Oronsky B, Knox S, Cabrales P, Oronsky A, Reid TR. Desperate times, desperate measures: the case for RRx-001 in the treatment of COVID-19. Semin Oncol. 2020;47(5):305–8.
pubmed: 32718560
pmcid: 7341953
doi: 10.1053/j.seminoncol.2020.07.002