RRx-001 is a hypoxia-selective and blood-brain barrier-permeable epigenetic modulator[1]. RRx-001 can affect the metabolic processes of tumor cells by inhibiting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby increasing the level of intracellular oxidative stress[2]. In animal experiments, RRx-001 can serve as a radiosensitizer and is used in mechanistic studies regarding antitumor activity against multidrug-resistant tumors, as well as radioprotection and chemoprotection[3,4].
In vitro, treatment of IL-4 (10ng/mL) and IL-10 (20ng/mL)-polarized M2 mouse bone marrow-derived macrophages (BMDMs) with RRx-001 (2μM) for 24h effectively increased the mRNA expression levels of M1 markers CD80 and CD86, promoting the polarization of M2 macrophages toward the M1 phenotype[5]. Treatment of human colon cancer Caco2 cells with RRx-001 (5μg/mL) for 4, 8, 16, and 24h effectively enhanced Nrf2 protein accumulation and nuclear translocation[6].
In vivo, pretreatment of C57BL/6 mice with RRx-001 (2.5, 5, 10mg/kg; once daily) via intraperitoneal injection for 7 days, followed by stereotactic injection of lipopolysaccharide (LPS, 1mg/kg) into the substantia nigra pars compacta (SNpc) on day 8 for 6h, dose-dependently reduced the mRNA expression levels of pro-inflammatory factors such as iNOS, COX-2, IL-6, and TNF-α in the substantia nigra[7].
References:[1] FINE H, REID T, CAROEN S, et al. A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide+/-RRx-001 in newly diagnosed glioblastoma[J]. Frontiers in Oncology, 2023, 13: 1176448.
[2] GU X, MU C, ZHENG R, et al. The cancer antioxidant regulation system in therapeutic resistance[J]. Antioxidants, 2024, 13(7): 778.
[3] ORONSKY B, SCICINSKI J, NING S, et al. RRx-001, A novel dinitroazetidine radiosensitizer[J]. Investigational New Drugs, 2016, 34(3): 371-377.
[4] ORONSKY B, GUO X, WANG X, et al. Discovery of RRx-001, a Myc and CD47 downregulating small molecule with tumor targeted cytotoxicity and healthy tissue cytoprotective properties in clinical development[J]. Journal of Medicinal Chemistry, 2021, 64(11): 7261-7271.
[5] CABRALES P. RRx-001 acts as a dual small molecule checkpoint inhibitor by downregulating CD47 on cancer cells and SIRP-α on monocytes/macrophages[J]. Translational Oncology, 2019, 12(4): 626-632.
[6] ORONSKY B, SCRIBNER C, AGGARWAL R, et al. RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition[J]. Journal of Cancer Research and Clinical Oncology, 2019, 145(8): 2045-2050.
[7] FANG J, SHE J, LIN F, et al. RRx-001 exerts neuroprotection against LPS-induced microglia activation and neuroinflammation through disturbing the TLR4 pathway[J]. Frontiers in Pharmacology, 2022, 13: 889383.