The Addition of Manganese Porphyrins during Radiation Inhibits Prostate Cancer Growth and Simultaneously Protects Normal Prostate Tissue from Radiation Damage

Abstract

Radiation therapy is commonly used for prostate cancer treatment; however, normal tissues can be damaged from the reactive oxygen species (ROS) produced by radiation. In separate reports, we and others have shown that manganese porphyrins (MnPs), ROS scavengers, protect normal cells from radiation-induced damage but inhibit prostate cancer cell growth. However, there have been no studies demonstrating that MnPs protect normal tissues, while inhibiting tumor growth in the same model. LNCaP or PC3 cells were orthotopically implanted into athymic mice and treated with radiation (2 Gy, for 5 consecutive days) in the presence or absence of MnPs. With radiation, MnPs enhanced overall life expectancy and significantly decreased the average tumor volume, as compared to the radiated alone group. MnPs enhanced lipid oxidation in tumor cells but reduced oxidative damage to normal prostate tissue adjacent to the prostate tumor in combination with radiation. Mechanistically, MnPs behave as pro-oxidants or antioxidants depending on the level of oxidative stress inside the treated cell. We found that MnPs act as pro-oxidants in prostate cancer cells, while in normal cells and tissues the MnPs act as antioxidants. For the first time, in the same in vivo model, this study reveals that MnPs enhance the tumoricidal effect of radiation and reduce oxidative damage to normal prostate tissue adjacent to the prostate tumor in the presence of radiation. This study suggests that MnPs are effective radio-protectors for radiation-mediated prostate cancer treatment.

The manganese(III) porphyrin MnTnHex-2-PyP5+ modulates intracellular ROS and breast cancer cell migration: Impact on doxorubicin-treated cells

“…Recently, an in vivo study conducted by Chatterjee el al. [40] showed that MnTE-2-PyP did not affect the metastatic progression of PC3 cells in an orthotopic prostate tumor model. On the other hand, in a mouse D-245MG glioma xenograft model, down-regulation of metastatic pathways was observed upon treatment with MnP + radiation vs radiation only [41] .…”

Superoxide Dismutases (SODs) and SOD Mimetics

“…This review is focused on understanding the spatiotemporal nature of MnSOD regulation in the context of a changing tumor microenvironment, which is necessary to improve the design of oxidant- or antioxidant-based therapeutic strategies for the treatment of cancer. In primary research articles by Chatterjee et al [ 8 ] and Heer et al [ 9 ], these investigators use SOD mimetics to enhance anti-cancer treatment. Chatterjee et al [ 8 ] demonstrate that SOD mimetics, in combination with radiation, inhibit prostate cancer growth while simultaneously protecting the normal prostate tissue from radiation damage.…”

“…In primary research articles by Chatterjee et al [ 8 ] and Heer et al [ 9 ], these investigators use SOD mimetics to enhance anti-cancer treatment. Chatterjee et al [ 8 ] demonstrate that SOD mimetics, in combination with radiation, inhibit prostate cancer growth while simultaneously protecting the normal prostate tissue from radiation damage. Heer et al [ 9 ] enhance the anti-tumor effect of pharmacological ascorbate with the addition of SOD mimetics by enhancing hydrogen peroxide levels in the tumor.…”

MnTnBuOE-2-PyP treatment protects from radioactive iodine (I-131) treatment-related side effects in thyroid cancer

“…It has been previously shown that such MnPs protect from external beam radiation-induced salivary gland damage in head and neck cancer, but does not protect head and neck tumors from radiation-induced killing (Ashcraft et al 2015). Recent work has indicated that the MnPs act as a pro-oxidant in cancer cells by taking advantage of impaired antioxidant systems that allow accumulation of hydrogen peroxide to toxic levels, which results in the alteration of cell signaling and promotes cancer cell death (Kosmacek et al 2016;Tong et al 2016;Chatterjee et al 2018). The focus of the present study was to determine if MnTnBuOE-2-PyP could also be a highly effective and nontoxic radioprotective agent for therapeutic I-131 exposure.…”