The Antioxidant, MnTE-2-PyP, Prevents Side-Effects Incurred by Prostate Cancer Irradiation

Abstract

Prostate cancer is the most commonly diagnosed cancer, with an estimated 240,000 new cases reported annually in the United States. Due to early detection and advances in therapies, more than 90% of patients will survive 10 years post diagnosis and treatment. Radiation is a treatment option often used to treat localized disease; however, while radiation is very effective at killing tumor cells, normal tissues are damaged as well. Potential side-effects due to prostate cancer-related radiation therapy include bowel inflammation, erectile dysfunction, urethral stricture, rectal bleeding and incontinence. Currently, radiation therapy for prostate cancer does not include the administration of therapeutic agents to reduce these side effects and protect normal tissues from radiation-induced damage. In the current study, we show that the small molecular weight antioxidant, MnTE-2-PyP, protects normal tissues from radiation-induced damage in the lower abdomen in rats. Specifically, MnTE-2-PyP protected skin, prostate, and testes from radiation-induced damage. MnTE-2-PyP also protected from erectile dysfunction, a persistent problem regardless of the type of radiation techniques used because the penile neurovascular bundles lay in the peripheral zones of the prostate, where most prostate cancers reside. Based on previous studies showing that MnTE-2-PyP, in combination with radiation, further reduces subcutaneous tumor growth, we believe that MnTE-2-PyP represents an excellent radioprotectant in combination radiotherapy for cancer in general and specifically for prostate cancer.

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“…n = 8 rats/group, ''*'' denotes a significant difference from PBS group, p = 0.05, and ''#'' denotes a significant difference from RAD group, p = 0.05. The MnP also prevented testes shrinkage (C), hair loss (not shown), and the damage to prostate tissue (not shown) (192). The oxidative stress is demonstrated as the increase in NAPDH oxidase expression (F), macrophage infiltration (ED-1) (E), and Nrf-2 (the primary cellular defense against the cytotoxic effects of oxidative stress) up-regulation (D) (136) Nrf-2, nuclear factor-erythroid-derived 2-like 2.…”

“…The MnTE-2-PyP 5 + fully reversed the erectile dysfunction as a consequence of prostate tumor radiation (Fig. 23) (192). Mice were irradiated for five sequential days at 7.5 Gy/day in a lower pelvic region, which mimics the irradiation scheme of prostate tumor patients.…”

“…MnP protects against prostate radiation-induced injury to male reproductive system. The reversal of erectile dysfunction and the reduction in testes shrinkage by MnTE-2-PyP 5 + , induced after rat prostate radiation (A-C) as a consequence of radiation-induced oxidative stress (D-F) (192). Intracavernous pressure (ICP) was obtained after cavernous nerve stimulation as a measurement of erectile function 12 weeks postirradiation.…”

MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene

“…We have previously published that MnTE-2-PyP protects the urogenital region from radiation damage. In particular, MnTE-2-PyP protects from erectile dysfunction and testicular atrophy after radiation exposure to the urogenital region [11]. However, there have been no in depth studies conducted to determine the effect of MnTE-2-PyP on human prostate tumors.…”

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“…Application of porphyrin antioxidants such as manganese porphyrins ( Figure 21) can also lead to reduction of oxidative stress and a cascade of cytokine activity and thereby mitigation of radiotherapy side effects. 274,275 Their whole therapeutic effect is based on achievement of individual effects. Manganese porphyrins catalytically neutralize oxidative stress stimulated molecules such as superoxide, peroxynitrite, carbonate radical and nitric oxide.…”