RRx-001
(Synonyms: ABDNAZ) 目录号 : GC32066
RRx-001 是一种源自航空航天的抗癌剂，具有产生活性氮物质 (RNS) 的化学作用，可导致表观遗传改变，例如癌细胞中的 DNA 甲基化和组蛋白乙酰化。
Cas No.:925206-65-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Human cancer cell lines HEP-G2, HT-29, CACO-2 |
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Preparation Method |
The MTT proliferation assay kit was used to detect cell growth and proliferation. 5 103 cells were seeded in each well of a 96-well plate, treated with (or without) compound (RRx-001) and cultured for up to 72 h. Then 10 µL was added to each well |
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Reaction Conditions |
5, 50, 100 mM RRx-001 for 72h |
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Applications |
RRx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. In all cancer cell lines tested, RRx-001 induced G6PD inhibition in a concentration dependent fashion. |
| Animal experiment [2]: | |
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Animal models |
Nude mice, male, 7-8 weeks old and 20-25 grams in body weight |
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Preparation Method |
Tumors were imaged for basal FLUC, RLUC, and mRFP signals 24 h before administration of RRx-001. Following injection with RRx-001, mice were imaged for RLUC signal by intravenous injection of 50 µg of coelenterazine at 8 and 24 h post-RRx-001 treatment. |
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Dosage form |
10 mg/kg RRx-001( i.v.) |
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Applications |
Mice were imaged for ARE-FLUC expression 24 h before and after RRx-001 administration. Results showed that a single dose of 10 mg/kg RRx-001 inhibited tumor growth and produced a tumor volume quadrupling time of 5.7±1.3 days compared to 3.3±0.7 days of vehicle control group. |
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References: [1].Oronsky B, Scicinski J, et,al.RRx-001, a novel clinical-stage chemosensitizer, radiosensitizer, and immunosensitizer, inhibits glucose 6-phosphate dehydrogenase in human tumor cells. Discov Med. 2016 Apr;21(116):251-65. PMID: 27232511. |
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RRx-001 is an aerospace-derived anticancer agent with reactive nitrogen species (RNS)-generating chemistry that leads to epigenetic alterations, such as DNA methylation and histone acetylation in cancer cells[4,7]. Apart from epigenetic alterations, RRx-001 acts via pleiotropic mechanisms including redox signaling and redox-induced dysregulation of many different signal pathways such as Nrf2, p53, PARP cleavage, HIF1 alpha, and G6PD activity[5]. RRx-001 also triggers p53 and p21 activity in response to double-stranded DNA breaks as well as deregulates cancer cellular energetics and metabolism[6].
Rx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. In all cancer cell lines tested, RRx-001 induced G6PD inhibition in a concentration dependent fashion[1]. RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001[2]. The increase in the synthesis and release of cytokines and the up-regulation of pro-inflammatory factors in LPS-treated microglial cells were significantly reduced by RRx-001 pretreatment. As the most classical inflammatory pathways, NF-κB and MAPK signaling pathways were activated by LPS, but were inhibited by RRx-001[9].
Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway[2]. RRx-001 plays a role in short-term blood flow redistribution in tumors enriched in percutaneous cells and α-SMA vessels[3]. One hour following administration of 99mTc labeled RBCs treated with 10 mg/kg RRx-001, An approximate 2.0-fold and 1.5-fold increase in 99mTc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. An approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001[8].
References:
[1]. Oronsky B, Scicinski J, et,al. RRx-001, a novel clinical-stage chemosensitizer, radiosensitizer, and immunosensitizer, inhibits glucose 6-phosphate dehydrogenase in human tumor cells. Discov Med. 2016 Apr;21(116):251-65. PMID: 27232511.
[2]. Ning S, Sekar TV, et,al. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001. Oncotarget. 2015 Aug 28;6(25):21547-56. doi: 10.18632/oncotarget.4249. PMID: 26280276; PMCID: PMC4673285.
[3]. Oronsky B, Scicinski J, et,al. RRx-001, an epigenetic-based radio- and chemosensitizer, has vascular normalizing effects on SCCVII and U87 tumors. Clin Epigenetics. 2016 May 11;8:53. doi: 10.1186/s13148-016-0220-7. PMID: 27175220; PMCID: PMC4864927.
[4]. Ning S, Bednarski M, et,al.Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials. Cancer Res. 2012 May 15;72(10):2600-8. doi: 10.1158/0008-5472.CAN-11-2303. PMID: 22589277.
[5]. Magesh S, Chen Y, et,al. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev. 2012 Jul;32(4):687-726. doi: 10.1002/med.21257. Epub 2012 May 1. PMID: 22549716; PMCID: PMC3393814.
[6]. Oronsky B, Oronsky N, et,al. Episensitization: therapeutic tumor resensitization by epigenetic agents: a review and reassessment. Anticancer Agents Med Chem. 2014;14(8):1121-7. doi: 10.2174/1871520614666140418144610. PMID: 24893730; PMCID: PMC4262965.
[7]. Oronsky B, Scicinski J, et,al. RRx-001, A novel dinitroazetidine radiosensitizer. Invest New Drugs. 2016 Jun;34(3):371-7. doi: 10.1007/s10637-016-0326-y. Epub 2016 Feb 3. PMID: 26841903; PMCID: PMC4859863.
[8]. Jani VP, Asaro R, et,al. RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature. Int J Mol Sci. 2021 Apr 29;22(9):4713. doi: 10.3390/ijms22094713. PMID: 33946824; PMCID: PMC8124275.
[9].Fang J, She J, et,al. RRx-001 Exerts Neuroprotection Against LPS-Induced Microglia Activation and Neuroinflammation Through Disturbing the TLR4 Pathway. Front Pharmacol. 2022 Apr 6;13:889383. doi: 10.3389/fphar.2022.889383. PMID: 35462935; PMCID: PMC9020799.
RRx-001 是一种源自航空航天的抗癌剂，具有产生活性氮物质 (RNS) 的化学作用，可导致表观遗传改变，例如癌细胞中的 DNA 甲基化和组蛋白乙酰化[4,7]。除了表观遗传改变外，RRx-001 通过多效机制发挥作用，包括氧化还原信号和氧化还原诱导的许多不同信号通路失调，例如 Nrf2、p53、PARP 裂解、HIF1 α 和 G6PD 活性[5] . RRx-001 还会触发 p53 和 p21 活性以响应双链 DNA 断裂，并解除对癌细胞能量和代谢的调节[6]。
Rx-001 影响三种不同癌细胞系（即 Hep G2、CACO-2 和 HT-29）中的葡萄糖和 G6PD 酶活性。在所有测试的癌细胞系中，RRx-001 以浓度依赖性方式诱导 G6PD 抑制[1]。 RRx-001 介导 Nrf2 的核转位及其下游酶 HO-1 和 NQO1 在肿瘤细胞中的表达激活。 Nrf2 特异性 siRNA 对内在 Nrf2 表达的抑制增加了细胞对 RRx-001[2] 的敏感性。 RRx-001 预处理显着降低了 LPS 处理的小胶质细胞中细胞因子合成和释放的增加以及促炎因子的上调。作为最经典的炎症通路，NF-κB和MAPK信号通路被LPS激活，但被RRx-001[9]抑制。
在小鼠体外和体内共表达 pARE-萤火虫荧光素酶和 pCMV-海肾荧光素酶-mRFP 的肿瘤细胞的分子成像显示，RRx-001 以剂量和时间依赖性显着增加细胞中的 ARE-FLUC 信号方式，表明 RRx-001 是 Nrf2-ARE 信号通路的有效激活剂[2]。 RRx-001 在富含经皮细胞和 α-SMA 血管的肿瘤中的短期血流再分布中发挥作用[3]。施用用 10 mg/kg RRx-001 处理的 99mTc 标记的 RBC 后一小时，在 HEPG2 和 HT-29 肿瘤模型中，与载体对照相比，99mTc 标记的 RBC 分别增加了大约 2.0 倍和 1.5 倍。用 RRx-001[8] 治疗后，HEP-G2 和 HT-29 肿瘤重量分别减少了大约 40% 和 36%。
| Cas No. | 925206-65-1 | SDF | |
| 别名 | ABDNAZ | ||
| Canonical SMILES | BrCC(N1CC([N+]([O-])=O)([N+]([O-])=O)C1)=O | ||
| 分子式 | C5H6BrN3O5 | 分子量 | 268.02 |
| 溶解度 | DMSO : ≥ 100 mg/mL (373.11 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.7311 mL | 18.6553 mL | 37.3106 mL |
| 5 mM | 0.7462 mL | 3.7311 mL | 7.4621 mL |
| 10 mM | 0.3731 mL | 1.8655 mL | 3.7311 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor
Cell Mol Immunol 2021 Jun;18(6):1425-1436.PMID:33972740DOI:10.1038/s41423-021-00683-y.
The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.
RRx-001, A novel dinitroazetidine radiosensitizer
Invest New Drugs 2016 Jun;34(3):371-7.PMID:26841903DOI:10.1007/s10637-016-0326-y.
The 'holy grail' in radiation oncology is to improve the outcome of radiation therapy (RT) with a radiosensitizer-a systemic chemical/biochemical agent that additively or synergistically sensitizes tumor cells to radiation in the absence of significant toxicity. Similar to the oxygen effect, in which DNA bases modified by reactive oxygen species prevent repair of the cellular radiation damage, these compounds in general magnify free radical formation, leading to the permanent "fixation" of the resultant chemical change in the DNA structure. The purpose of this review is to present the origin story of the radiosensitizer, RRx-001, which emerged from the aerospace industry. The activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.
RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature
Int J Mol Sci 2021 Apr 29;22(9):4713.PMID:33946824DOI:10.3390/ijms22094713.
Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability. We next investigated the biomechanics of RBC adhesion in the context of local inflammatory cytokines after treatment with RRx-001 as a potential mechanism for preferential tumor aggregation. Human HEP-G2 and HT-29 tumor cells were subcutaneously implanted into nu/nu mice and were infused with RRx-001-treated and Technetium-99m (99mTc)-labeled blood. RBC adhesion was quantified in an in vitro human umbilical vein endothelial cell (HUVEC) assay under both normoxic and hypoxic conditions with administration of either lipopolysaccharide (LPS) or Tumor necrosis alpha (TNFα) to mimic the known inflammation in the tumor microenvironment. One hour following administration of 99mTc labeled RBCs treated with 10 mg/kg RRx-001, we observed an approximate 2.0-fold and 1.5-fold increase in 99mTc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. Furthermore, we observed an approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001. To quantify RBC adhesive potential, we determined τ50, or the shear stress required for 50% disassociation of RBCs from HUVECs. After administration of TNF-α under normoxia, τ50 was determined to be 4.5 dynes/cm2 (95% CI: 4.3-4.7 dynes/cm2) for RBCs treated with 10 μM RRx-001, which was significantly different (p < 0.05) from τ50 in the absence of treatment. Under hypoxic conditions, the difference of τ50 with (4.8 dynes/cm2; 95% CI: 4.6-5.1 dynes/cm2) and without (2.6 dynes/cm2; 95% CI: 2.4-2.8 dynes/cm2) 10 μM RRx-001 treatment was exacerbated (p = 0.05). In conclusion, we demonstrated that RBCs treated with RRx-001 preferentially aggregate in HEP-G2 and HT-29 tumors, likely due to interactions between RRx-001 and cysteine residues within RBCs. Furthermore, RRx-001 treated RBCs demonstrated increased adhesive potential to endothelial cells upon introduction of TNF-α and hypoxia suggesting that RRx-001 may induce preferential adhesion in the tumor but not in other tissues with endothelial dysfunction due to conditions prevalent in older cancer patients such as heart disease or diabetic vasculopathy.
RRx-001 Exerts Neuroprotection Against LPS-Induced Microglia Activation and Neuroinflammation Through Disturbing the TLR4 Pathway
Front Pharmacol 2022 Apr 6;13:889383.PMID:35462935DOI:10.3389/fphar.2022.889383.
Neuroinflammation plays an important role in the pathogenesis of many central nervous system diseases. Here, we investigated the effect of an anti-cancer compound RRx-001 on neuroinflammation and its possible new applications. BV2 cells and primary microglia cells were used to evaluate the role of RRx-001 in LPS-induced microglial activation and inflammatory response in vitro. And, we found that the increase in the synthesis and release of cytokines and the up-regulation of pro-inflammatory factors in LPS-treated microglial cells were significantly reduced by RRx-001 pretreatment. As the most classical inflammatory pathways, NF-κB and MAPK signaling pathways were activated by LPS, but were inhibited by RRx-001. Transcription of NLRP3 was also reduced by RRx-001. In addition, LPS induced oxidative stress by increasing the expression of Nox mediated by transcription factors NF-κB and AP-1, while RRx-001 pretreatment ameliorated Nox-mediated oxidative stress. LPS-induced activation of TAK1, an upstream regulator of NF-κB and MAPK pathways, was significantly inhibited by RRx-001 pretreatment, whereas recruitment of MyD88 to TLR4 was not affected by RRx-001. LPS-primed BV2 condition medium induced injury of primary neurons, and this effect was inhibited by RRx-001. Furthermore, we established a neuroinflammatory mouse model by stereotactic injection of LPS into the substantia nigra pars compacta (SNpc), and RRx-001 dose-dependently reduced LPS-induced microglial activation and loss of TH + neurons in the midbrain. In conclusion, the current study found that RRx-001 suppressed microglia activation and neuroinflammation through targeting TAK1, and may be a candidate for the treatment of neuroinflammation-related brain diseases.
RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials
Expert Opin Investig Drugs 2017 Jan;26(1):109-119.PMID:27935336DOI:10.1080/13543784.2017.1268600.
According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future.