The radioprotectant nano-genistein enhances radiotherapy efficacy of lung tumors in mice

BACKGROUND: Radiotherapy for non-small cell lung cancer (NSCLC) can be dose-limiting due to treatment-related toxicities. Genistein has been shown to be a robust radioprotective agent in preclinical models. A novel genistein oral nanosuspension formulation (nano-genistein) has demonstrated efficacy in mitigating radiation-induced lung damage in preclinical animal models. However, while those studies have confirmed that nano-genistein can protect normal lung tissue from radiation-induced toxicities, no studies have assessed the effect of nano-genistein on lung tumors. Here, we evaluated the impact of nano-genistein on the efficacy of radiation treatment of lung tumors in a mouse xenograft model. METHODS: Two separate studies were conducted utilizing human A549 cells implanted either dorsally within the upper torso or in the flank. Daily oral administration of nano-genistein (200 or 400 mg/kg/day) occurred prior to and after exposure to a single dose of thoracic or abdominal 12.5 Gy radiation. Tumor growth was monitored twice weekly, nano-genistein treatment continued for up to 20 weeks and histopathology of tissues was completed post euthanasia. RESULTS: Continuous nano-genistein dosing was safe across all study groups in both studies. Animals receiving nano-genistein better maintained body weight following irradiation compared to corresponding vehicle treated animals. Animals that received nano-genistein also had reduced tumor growth and improved normal lung histopathology compared to those receiving vehicle suggesting that nano-genistein does not protect tumors from radiotherapy but is radioprotective of the lungs. There were no treatment-related histopathological findings noted in the skin adjacent to the tumor, esophagus, or uterus. CONCLUSIONS: These results, including the safety following extended dosing, support the continued evaluation of nano-genistein as an adjunctive treatment for patients with NSCLC undergoing radiotherapy and serve as the basis of a phase 1b/2a multicenter clinical trial

The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase

Human cells express up to 9 active DNA cytosine deaminases with functions in adaptive and innate immunity. Many cancers manifest an APOBEC mutation signature and APOBEC3B (A3B) is likely the main enzyme responsible. Although significant numbers of APOBEC signature mutations accumulate in tumor genomes, the majority of APOBEC-catalyzed uracil lesions are probably counteracted in an error-free manner by the uracil base excision repair pathway. Here, we show that A3B-expressing cells can be selectively killed by inhibiting uracil DNA glycosylase 2 (UNG) and that this synthetic lethal phenotype requires functional mismatch repair (MMR) proteins and p53. UNG knockout human 293 and MCF10A cells elicit an A3B-dependent death. This synthetic lethal phenotype is dependent on A3B catalytic activity and reversible by UNG complementation. A3B expression in UNG-null cells causes a buildup of genomic uracil, and the ensuing lethality requires processing of uracil lesions (likely U/G mispairs) by MSH2 and MLH1 (likely noncanonical MMR). Cancer cells expressing high levels of endogenous A3B and functional p53 can also be killed by expressing an UNG inhibitor. Taken together, UNG-initiated base excision repair is a major mechanism counteracting genomic mutagenesis by A3B, and blocking UNG is a potential strategy for inducing the selective death of tumors.</p

Polyomavirus T Antigen Induces APOBEC3B Expression Using an LXCXE-Dependent and TP53-Independent Mechanism

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