MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells

Kosmacek, Elizabeth A.; Chatterjee, Arpita; Tong, Qiang; Lin, Chi; Oberley‐Deegan, Rebecca E.

doi:10.18632/oncotarget.8923

Cited by 23 publications

(35 citation statements)

References 55 publications

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“…In our previously published study, we reported that MnTnBuOE-2-PyP, a sister compound of MnTE-2-PyP, can protect colorectal fibroblasts from 2 Gy radiation-induced damage (11). For the current study, we investigated the underlying mechanism of MnTE-2-PyP in protecting normal tissue from radiation-induced fibrosis and senescence.…”

Section: Discussionmentioning

confidence: 99%

“…Previously reported studies have shown that MnTE-2-PyP can protect from radiation-induced external tissue damage in rats (9), without protecting the tumor (10). MnTnBuOE-2-PyP, a sister compound of MnTE-2-PyP, has been shown to protect normal colorectal fibroblast cells, while simultaneously enhancing the cytotoxic effects of radiation or chemotherapeutic agents on colorectal cancer cells (11). Understanding the mechanism by which a compound works is helpful for successful clinical use.…”

Section: Introductionmentioning

confidence: 99%

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MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1 Signaling Pathway

2017

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Prostate cancer patients who undergo radiotherapy frequently suffer from side effects caused by radiation-induced damage to normal tissues adjacent to the tumor. Exposure of these normal cells during radiation treatment can result in tissue fibrosis and cellular senescence, which ultimately leads to postirradiation-related chronic complications including urinary urgency and frequency, erectile dysfunction, urethral stricture and incontinence. Radiation-induced reactive oxygen species (ROS) have been reported as the most potent causative factor for radiation damage to normal tissue. While MnTE-2-PyP, a ROS scavenger, protects normal cells from radiation-induced damage, it does not protect cancer cells during radiation treatment. However, the mechanism by which MnTE-2-PyP provides protection from radiation-induced fibrosis has been unclear. Our current study reveals the underlying molecular mechanism of radiation protection by MnTE-2-PyP in normal mouse prostate fibroblast cells. To investigate the role of MnTE-2-PyP in normal tissue protection after irradiation, primary prostate fibroblasts from C57BL/6 mice were cultured in the presence or absence of MnTE-2-PyP and exposed to 2 Gy of X rays. We found that MnTE-2-PyP could protect primary prostate fibroblasts from radiation-induced activation, as measured by the contraction of collagen discs, and senescence, detected by beta-galactosidase staining. We observed that MnTE-2-PyP inhibited the TGF-β-mediated fibroblast activation pathway by downregulating the expression of TGF-β receptor 2, which in turn reduced the activation and/or expression of SMAD2, SMAD3 and SMAD4. As a result, SMAD2/3-mediated transcription of profibrotic markers was reduced by MnTE-2-PyP. Due to the inhibition of the TGF-β pathway, fibroblasts treated with MnTE-2-PyP could resist radiation-induced activation and senescence. NADPH oxidase 4 (NOX4) expression is upregulated after irradiation and produces ROS. As was observed with MnTE-2-PyP treatment, NOX4−/− fibroblasts were protected from radiation-induced fibroblast activation and senescence. However, NOX4−/− fibroblasts had reduced levels of active TGF-β1, which resulted in decreased TGF-β signaling. Therefore, our data suggest that reduction of ROS levels, either by MnTE-2-PyP treatment or by eliminating NOX4 activity, significantly protects normal prostate tissues from radiation-induced tissue damage, but that these approaches work on different components of the TGF-β signaling pathway. This study proposes a crucial insight into the molecular mechanism executed by MnTE-2-PyP when utilized as a radioprotector. An understanding of how this molecule works as a radioprotector will lead to a better controlled mode of treatment for post therapy complications in prostate cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1 Signaling Pathway

2017

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“…Depending on the environment, MnPs can act in either an antioxidant or pro-oxidant capacity. MnBuOE has been shown to sensitize tumor cells to chemotherapy and radiotherapy while protecting normal tissue by modulating tissue redox [17,21].…”

Section: Introductionmentioning

confidence: 99%

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

McElroy

Brown

Kiffer

et al. 2020

IJMS

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Background: Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin superoxide dismutase mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. Methods: Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. Results: MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups.

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“…Cationic manganese-(Mn-) substituted N-pyridylporphyrins (MnPs) were initially developed as powerful SOD mimic, and MnPs, which regulate intracellular redox environment, have reached the stage of clinical application [12]. It has been reported that intraperitoneal injection of MnTE-2-PyP (BMX-010, AEOL10113) during radiotherapy performed on the lower abdomen of rats significantly reduced radiation damage to normal tissues such as the skin, prostate, and testis [13], while a similar compound, MnTnBuOE-2-PyP (BMX-001), protected normal tissue effectively while enhancing radiotherapy and chemotherapy treatment in colorectal cancer [14]. It is noteworthy that MnPs have been reported to improve epidermal wound healing.…”

Section: Introductionmentioning

confidence: 99%

Superoxide Dismutase Mimic, MnTE-2-PyP Enhances Rectal Anastomotic Strength in Rats after Preoperative Chemoradiotherapy

Wang

Luo

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Rectal cancer is one of the malignant diseases with high morbidity and mortality in the world. Currently, surgical resection is the main treatment method, and preoperative chemoradiotherapy (CRT) is widely used in clinical application to increase resectability and decrease the local recurrence rate. However, CRT increases the risk of colon anastomotic leak, and currently, there are no FDA approved treatments against this side effect. It is essential to develop new drugs to reduce postoperative anastomotic leak after preoperative CRT. Methods. 90 rats underwent standard resection and intestine anastomosis treatment and were divided into six groups for different treatments. During the relaparotomy, bursting pressure of anastomosis was measured and intestinal segments were taken for histopathologic examination and biochemical analyses. RT-PCR and ELISA were applied to measure matrix metalloproteinase (MMP) mRNA and protein levels. Blood vessels were observed by immunohistochemistry, and collagen deposition was observed by Picrosirius Red staining. Results. Preoperative CRT reduced the postoperative anastomotic strength. MnTE-2-PyP increased the bursting pressure and hydroxyproline levels of intestine anastomosis after CRT treatment. Mechanically, MnTE-2-PyP decreased the MMP levels and increased microvessel density (MVD) and collagen deposition. The MMP inhibitor doxycycline had a positive effect on anastomosis healing, but was inferior to MnTE-2-PyP. Conclusions. MnTE-2-PyP enhanced intestine anastomotic strength in rats with preoperative CRT. Specifically, MnTE-2-PyP decreased MMP levels and increased MVD in anastomosis. Therefore, MnTE-2-PyP may be helpful in the prevention of anastomotic leak after preoperative CRT.

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MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells

Cited by 23 publications

References 55 publications

MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1 Signaling Pathway

MnTE-2-PyP Treatment, or NOX4 Inhibition, Protects against Radiation-Induced Damage in Mouse Primary Prostate Fibroblasts by Inhibiting the TGF-Beta 1 Signaling Pathway

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

Superoxide Dismutase Mimic, MnTE-2-PyP Enhances Rectal Anastomotic Strength in Rats after Preoperative Chemoradiotherapy

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