Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2–/– (C57BL/6) Mice

Abstract

We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2−/−mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10–12 weeks old) Fancd2+/+, Fancd2+/− and Fancd2−/− mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/ mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2−/− mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2+/+ mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2−/− mice, as well as wild-type mice.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…Other mitochondria-targeted agents, including derivatives of TEMPOL, were shown to protect against radiation-induced oxidative damage in normal cells and radiosensitize the glioma cells. 412,413,419,421 …”

Malignant Transformation of Fanconi Anemia Complementation Group D2-deficient (Fancd2−/−) Hematopoietic Progenitor Cells by a Single HPV16 Oncogene

“…Patients with FA demonstrate evolution of acute myeloid leukemia resulting from the malignant transformation of bone marrow of hematopoietic stem cells (9). The use of the long-term bone marrow culture system mouse model of FA has a great potential value for elucidation of the sequential mutation mechanisms involved in evolution of hematopoietic malignancies (5)(6)(7). Further studies should elucidate the sequential mutational changes in Fancd2 −/− long-term bone marrow cultures and derived hematopoietic cell lines which lead to final malignant transformation by a single HPV or other viral or microbial factors including other oncogenes.…”

Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia

“…In addition, several groups are studying the use of radiation protector agents. Animal models using FANCD2 −/− (FVB/N) mice, FANCD2 −/− (C57BL/6) mice, and FANCA −/− and FANCG −/− mice showed that the intraoral administration of JP4‐039 (GS‐nitroxide) before each radiation treatment improves local normal tissue radiosensitivity and distant bone marrow suppression. These results support the need for clinical trials with this agent for future use in clinical RT for patients with FA.…”