Roughly 1.5 million US men living today have been treated with radiation therapy for prostate cancer and the number is expected to increase. The majority of these patients will suffer significant reduction in quality of life (i.e., erectile dysfunction, incontinence and proctitis) ad there are no FDA approved treatments to protect normal pelvic tissues from radiation-induced damage. Radiation exposure leads to free radical-mediated oxidative damage to normal tissues leading to fibrosis. The activation of p300 helps to drive persistent inflammation and fibrosis after irradiation. Cancer cells have increased metabolic production of reactive oxygen species (ROS) and p300 activity, relative to normal cells, which have been shown to drive cancer progression. Thus, suppressing radiation-induced ROS and p300 activity can act as both a radio-protector in normal tissues while inhibiting pro-survival and progression pathways in cancer cells. MnTE-2-PyP is a small molecule antioxidant, which scavenges a variety of ROS and reduces p300 activity. Preliminary data demonstrate that MnTE-2-PyP protects urogenital tissues from radiation-induced damage, while enhancing prostate cancer killing. The overall hypothesis of this proposal is that MnTE-2-PyP both scavenges ROS and inhibits p300 activity, which protects normal tissue injury by suppressing fibrosis while at the same time inhibiting tumor progression.
Specific Aim 1 will determine whether MnTE-2-PyP protects normal pelvic tissues from radiation-induced inflammation by inhibiting both NADPH oxidase derived ROS and p300 activity. We will determine whether: 1. MnTE-2-PyP protects normal tissues from radiation damage by inhibiting ROS and p300 2. MnTE-2-PyP through ROS scavenging and p300 inhibition prevents pro-fibrotic signaling in fibroblasts exposed to irradiation 3. MnTE-2-PyP protects normal tissues by inhibiting Th2 inflammatory response by inhibiting NADPH oxidase- derived ROS and p300 activity.
Specific Aim 2 will determine whether MnTE-2-PyP inhibits the progression of irradiated prostate cancer cells both in vitro and in vivo via ROS scavenging and p300 inhibition. In this aim it will be demonstrated that: 1. MnTE-2-PyP sensitizes prostate cancer cells to irradiation in vitro and in vivo 2. The manipulation of p300 and/or ROS affects the ability of MnTE-2-PyP to inhibit pro-survival and pro-angiogenic pathways necessary for tumor survival. 3. MnTE-2-PyP inhibits tumor growth and metastasis in an irradiated orthotopic xenograft model while protecting normal tissues. The completion of the studies will provide an in depth mechanistic understanding of the mechanisms by which MnTE-2-PyP inhibits normal tissue injury, while reducing prostate cancer growth during prostate cancer radiotherapy. Understanding how MnTE-2-PyP works as a radio-protector, can lead to the development more targeted therapies to enhance treatment outcomes in prostate cancer radiotherapy.
Patients receiving radiotherapy for prostate cancer often suffer from debilitating side-effects due to irradiation damage to tissues surrounding the tumor. Currently, there are no radio-protectors approved to be used with prostate cancer radiotherapy. An antioxidant drug, developed in our laboratory, shows promise as an effective radio-protector because the drug protects healthy tissues from radiation damage while, simultaneously, inhibiting growth of prostate cancer.
|Chatterjee, Arpita; Kosmacek, Elizabeth A; Oberley-Deegan, Rebecca E (2017) 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. Radiat Res 187:367-381|
|Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:|
|Tong, Qiang; Weaver, Michael R; Kosmacek, Elizabeth A et al. (2016) 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. Free Radic Biol Med 94:185-94|
|Kosmacek, Elizabeth A; Chatterjee, Arpita; Tong, Qiang et al. (2016) MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells. Oncotarget 7:34532-45|
|Tong, Qiang; Zhu, Yuxiang; Galaske, Joseph W et al. (2016) MnTE-2-PyP modulates thiol oxidation in a hydrogen peroxide-mediated manner in a human prostate cancer cell. Free Radic Biol Med 101:32-43|