Mechanism of the Antitumor and Radiosensitizing Effects of a Manganese Porphyrin, MnHex-2-PyP

Abstract

Combination treatment with MnTnHex-2-PyP and IR substantially reduced cell viability, clonogenic cell survival, and DNA damage repair and synergistically increased IR-induced apoptosis of 4T1 and B16 cells. MnTnHex-2-PyP in combination with IR caused a significant delay in growth of 4T1 and B16 xenograft tumors. MnTnHex-2-PyP dose-dependently enhanced IR-mediated production of HO-derived species, but not superoxide. Catalase overexpression reversed MnTnHex-2-PyP-enhanced ROS production and apoptosis. Demonstrated suppression of phosphorylation of several mitogen-activated protein (MAP) kinases and activation of NF-κB by MnTnHex-2-PyP/IR, which presumably inhibited activation of the antiapoptotic pathway, are in agreement with our other data on the apoptosis of cancer cells. Innovation and Conclusions: MnTnHex-2-PyP exerted a radiosensitizing effect on 4T1 and B16 tumor models in vitro and in vivo via pro-oxidative actions and therefore bears a large therapeutic potential. When combined with IR, it attenuated DNA damage repair and triggered a shift from prosurvival pathways to apoptotic cell death, likely due to increased ROS production and disturbed cellular redox balance, acting at the level of nuclear factor κB (NF-κB). Antioxid. Redox Signal. 27, 1067-1082.

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

“…Image acquisition and analyses were conducted as described previously [37]. Briefly, 2 × 104 MDA-MB-231 cells were seeded on a cover slip (Marinfild Inc., Rochester, NY, USA) a day before irradiation.…”

Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation

“…Based on impressive therapeutic efficacy in different cellular and animal models of oxidative stress injury [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], high lipophilicity [ 6 , 29 , 35 ], high mitochondrial accumulation [ 6 , 36 ] and good safety/toxicity profile [ 6 , 7 , 9 , 35 ], the potent superoxide dismutase (SOD) mimetic and redox-active drug, manganese (III) meso- tetrakis ( N -hexylpyridinium-2-yl) porphyrin, MnTnHex-2-PyP 5+ (hexyl), was chosen as a mitigator in this nonhuman primate (NHP) model of pulmonary radiation injury ( Figure 1 ). In a rat model of lung radiation injury, we have shown previously that MnTnHex-2-PyP 5+ was superior to its ethyl analogs, Mn(III) meso -tetrakis( N -ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP 5+ (compound name: AEOL10113, BMX-010), as it mitigated radiation-induced lung injury when given at a 120-fold lower dose of 0.05 mg/kg/day for 2 weeks starting at 2 h after irradiation [ 27 , 28 ].…”

“…The lipophilicity of hexyl is the highest within the class of water-soluble cationic N -alkylpyridylporphyrins presently explored [ 6 , 29 , 38 ]. Therefore, MnTnHex-2-PyP 5+ distributes in all tissues thus far studied to higher levels than MnTE-2-PyP 5+ [ 7 , 35 , 39 ], and is thus up to 120-fold more efficacious in different animal and cellular models, such as SOD-deficient Escherichia coli and Saccharomyces cerevisiae , yeast, pain, cerebral palsy, stroke, subarachnoid hemorrhage, ischemia/reperfusion models and ataxia telangiectasia ( Figure 1 ) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 37 , 40 ]. Such high efficacy allows for ~16-fold larger therapeutic window of MnTnHex-2-PyP 5+ than of MnTE-2-PyP 5+ (see details further below in Introduction) [ 6 , 9 , 35 ].…”

“…Such high efficacy allows for ~16-fold larger therapeutic window of MnTnHex-2-PyP 5+ than of MnTE-2-PyP 5+ (see details further below in Introduction) [ 6 , 9 , 35 ]. In addition to normal tissue radioprotection, the radiosensitization of brain, melanoma and breast tumors with hexyl was also demonstrated in mouse models [ 6 , 8 ]. Hexyl and its analogs accumulate in mitochondria [ 6 , 15 , 37 ] and there mimic the superoxide dismutase isoform, MnSOD [ 6 , 15 , 18 , 23 , 40 , 41 ].…”

Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation

“…After irradiation, injection of VPA continued every 3 days until the day before sacrifice to keep the effect of VPA active in the mice. Tumor volumes were measured every 3 days with calipers and calculated according to following formula: volume = L × ( W ) 2 × 1/2 ( L , length in mm; W , width in mm) 27 , 63 , 64 . The animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Samsung Biomedical Research Institute, which is accredited by an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC, protocol number H-A9–003).…”