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Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

ABSTRACT: Normal tissue damage after head and neck radiotherapy involves a continuum of pathologic events to the mucosa, tongue and salivary glands. We examined the radioprotective effects of MnBuOE, a redox-active manganese porphyrin, at three stages of normal tissue damage: immediate (leukocyte endothelial cell [L/E] interactions), early (mucositis) and late (xerostomia and fibrosis) after treatment. In this study, mice received 0 or 9 Gy irradiation to the oral cavity and salivary glands ± MnBuOE treatment. Changes in leukocyte-endothelial cell interactions were measured 24 h postirradiation. At 11 days postirradiation, mucositis was assessed with a cathepsin-sensitive near-infrared optical probe. Stimulated saliva production was quantified at 11 weeks postirradiation. Finally, histological analyses were conducted to assess the extent of long-term effects in salivary glands at 12 weeks postirradiation. MnBuOE reduced oral mucositis, xerostomia and salivary gland fibrosis after irradiation. Additionally, although we have previously shown that MnBuOE does not interfere with tumor control at high doses when administered with radiation alone, most head and neck cancer patients will be treated with the combinations of radiotherapy and cisplatin. Therefore, we also evaluated whether MnBuOE would protect tumors against radiation and cisplatin using tumor growth delay as an endpoint. Using a range of radiation doses, we saw no evidence that MnBuOE protected tumors from radiation and cisplatin. We conclude that MnBuOE radioprotects normal tissue at both early and late time points, without compromising anti-tumor effects of radiation and cisplatin.

SUBMITTER: Birer SR

PROVIDER: S-EPMC5559715 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

Birer Samuel R SR Lee Chen-Ting CT Choudhury Kingshuk Roy KR Young Kenneth H KH Spasojevic Ivan I Batinic-Haberle Ines I Crapo James D JD Dewhirst Mark W MW Ashcraft Kathleen A KA

Radiation research 20170518 1

Normal tissue damage after head and neck radiotherapy involves a continuum of pathologic events to the mucosa, tongue and salivary glands. We examined the radioprotective effects of MnBuOE, a redox-active manganese porphyrin, at three stages of normal tissue damage: immediate (leukocyte endothelial cell [L/E] interactions), early (mucositis) and late (xerostomia and fibrosis) after treatment. In this study, mice received 0 or 9 Gy irradiation to the oral cavity and salivary glands ± MnBuOE treat ...[more]

PMID: 28517962

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Project description:SignificanceAfter approximatelty three decades of research, two Mn(III) porphyrins (MnPs), MnTE-2-PyP5+ (BMX-010, AEOL10113) and MnTnBuOE-2-PyP5+ (BMX-001), have progressed to five clinical trials. In parallel, another similarly potent metal-based superoxide dismutase (SOD) mimic-Mn(II)pentaaza macrocycle, GC4419-has been tested in clinical trial on application, identical to that of MnTnBuOE-2-PyP5+-radioprotection of normal tissue in head and neck cancer patients. This clearly indicates that Mn complexes that target cellular redox environment have reached sufficient maturity for clinical applications. Recent Advances: While originally developed as SOD mimics, MnPs undergo intricate interactions with numerous redox-sensitive pathways, such as those involving nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (Nrf2), thereby impacting cellular transcriptional activity. An increasing amount of data support the notion that MnP/H2O2/glutathione (GSH)-driven catalysis of S-glutathionylation of protein cysteine, associated with modification of protein function, is a major action of MnPs on molecular level.Critical issuesDifferential effects of MnPs on normal versus tumor cells/tissues, which support their translation into clinic, arise from differences in their accumulation and redox environment of such tissues. This in turn results in different yields of MnP-driven modifications of proteins. Thus far, direct evidence for such modification of NF-κB, mitogen-activated protein kinases (MAPK), phosphatases, Nrf2, and endogenous antioxidative defenses was provided in tumor, while indirect evidence shows the modification of NF-κB and Nrf2 translational activities by MnPs in normal tissue.Future directionsStudies that simultaneously explore differential effects in same animal are lacking, while they are essential for understanding of extremely intricate interactions of metal-based drugs with complex cellular networks of normal and cancer cells/tissues.

Project description:The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell's response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2's role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-?/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ?Np63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

Project description:Cationic Mn porphyrins are among the most potent catalytic antioxidants and/or cellular redox modulators. Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl(5)) is the Mn porphyrin most studied in vivo and has successfully rescued animal models of a variety of oxidative stress-related diseases. The stability of an authentic MnTE-2-PyPCl(5) sample was investigated hereon by thermogravimetric, derivative thermogravimetric, and differential thermal analyses (TG/DTG/DTA), under dynamic air, followed by studies at selected temperatures to evaluate the decomposition path and appropriate conditions for storage and handling of these materials. All residues were analyzed by thin-layer chromatography (TLC) and UV-vis spectroscopy. Three thermal processes were observed by TG/DTG. The first event (endothermic) corresponded to dehydration, and did not alter the MnTE-2-PyPCl(5) moiety. The second event (endothermic) corresponded to the loss of EtCl (dealkylation), which was characterized by gas chromatography-mass spectrometry. The residue at 279°C had UV-vis and TLC data consistent with those of the authentic, completely dealkylated analog, MnT-2-PyPCl. The final, multi-step event corresponded to the loss of the remaining organic matter to yield Mn(3)O(4) which was characterized by IR spectroscopy. Isothermal treatment at 188°C under static air for 3h yielded a mixture of partially dealkylated MnPs and traces of the free-base, dealkylated ligand, H(2)T-2-PyP, which reveals that dealkylation is accompanied by thermal demetallation under static air conditions. Dealkylation was not observed if the sample was heated as a solid or in aqueous solution up to ?100°C. Whereas moderate heating changes sample composition by loss of H(2)O, the dehydrated sample is indistinguishable from the original sample upon dissolution in water, which indicates that catalytic activity (on Mn basis) remains unaltered. Evidently, dealkylation at high temperature compromises sample activity.

Project description:PurposeFor decades, Dr. John Moulder has been a leading radiation biologist and one of the few who consistently supported the study of normal tissue responses to radiation. His meticulous modeling and collaborations across the field have offered a prime example of how research can be taken from the bench to the bedside and back, with the ultimate goal of providing benefit to patients. Much of the focus of John's work was on mitigating damage to the kidney, whether as the result of accidental or deliberate clinical exposures. Following in his footsteps, we offer here a brief overview of work conducted in the field of radiation-induced bladder injury. We then describe our own preclinical experimental studies which originated as a response to reports from a clinical genome-wide association study (GWAS) investigating genomic biomarkers of normal tissue toxicity in prostate cancer patients treated with radiotherapy. In particular, we discuss the use of Renin-Angiotensin System (RAS) inhibitors as modulators of injury, agents championed by the Moulder group, and how RAS inhibitors are associated with a reduction in some measures of toxicity. Using a murine model, along with precise CT-image guided irradiation of the bladder using single and fractionated dosing regimens, we have been able to demonstrate radiation-induced functional injury to the bladder and mitigation of this functional damage by an inhibitor of angiotensin-converting enzyme targeting the RAS, an experimental approach akin to that used by the Moulder group. We consider our scientific trajectory as a bedside-to-bench approach because the observation was made clinically and investigated in a preclinical model; this experimental approach aligns with the exemplary career of Dr. John Moulder.ConclusionsDespite the differences in functional endpoints, recent findings indicate a commonality between bladder late effects and the work in kidney pioneered by Dr. John Moulder. We offer evidence that targeting the RAS pathway may provide a targetable pathway to reducing late bladder toxicity.

Dataset Information

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

Publications

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

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