Background
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].
参考文献:
[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%。
Protocol
| Cell experiment [1]: |
|
Cell lines
|
Human cancer cell lines HEP-G2, HT-29, CACO-2
|
|
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
|
|
Reaction Conditions
|
5, 50, 100 mM RRx-001 for 72h
|
|
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]: |
|
Animal models
|
Nude mice, male, 7-8 weeks old and 20-25 grams in body weight
|
|
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.
|
|
Dosage form
|
10 mg/kg RRx-001( i.v.)
|
|
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.
|
|
参考文献:
[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.
|
没有评价数据