MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells
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Elizabeth A. Kosmacek1, Arpita Chatterjee1, Qiang Tong1, Chi Lin2, Rebecca E. Oberley-Deegan1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
2Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
Rebecca E. Oberley-Deegan, email: [email protected]
Keywords: MnTnBuOE-2-PyP, radiation, fibroblast, colorectal cancer, oxidative stress
Received: March 01, 2016 Accepted: March 31, 2016 Published: April 22, 2016
Manganese porphyrins have been shown to be potent radioprotectors in a variety of cancer models. However, the mechanism as to how these porphyrins protect normal tissues from radiation damage still remains largely unknown. In the current study, we determine the effects of the manganese porphyrin, MnTnBuOE-2-PyP, on primary colorectal fibroblasts exposed to irradiation. We found that 2 Gy of radiation enhances the fibroblasts’ ability to contract a collagen matrix, increases cell size and promotes cellular senesence. Treating fibroblasts with MnTnBuOE-2-PyP significantly inhibited radiation-induced collagen contraction, preserved cell morphology and also inhibited cellular senescence. We further showed that MnTnBuOE-2-PyP enhanced the overall viability of the fibroblasts following exposure to radiation but did not protect colorectal cancer cell viability. Specifically, MnTnBuOE-2-PyP in combination with irradiation, caused a significant decrease in tumor clonogenicity. Since locally advanced rectal cancers are treated with chemoradiation therapy followed by surgery and non-metastatic anal cancers are treated with chemoradiation therapy, we also investigated the effects of MnTnBuOE-2-PyP in combination with radiation, 5-fluorouracil with and without Mitomycin C. We found that MnTnBuOE-2-PyP in combination with Mitomycin C or 5-fluorouracil further enhances those compounds’ ability to suppress tumor cell growth. When MnTnBuOE-2-PyP was combined with the two chemotherapeutics and radiation, we observed the greatest reduction in tumor cell growth. Therefore, these studies indicate that MnTnBuOE-2-PyP could be used as a potent radioprotector for normal tissue, while at the same time enhancing radiation and chemotherapy treatment for rectal and anal cancers.
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