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Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities.

Metformin is a biguanide currently used in the treatment of diabetes mellitus type 2. Besides its anti-glycemic effects, metformin has been reported to induce different cellular pleiotropic effects, depending on concentration and time of treatment. Here we report one administration of metformin (0.5 mM) has radioprotective effects in vitro on BJ human fibroblasts, increasing DNA damage repair and increasing SOD1 expression in the nucleus. Importantly, metformin (200 mg/kg) pre-administration for only 3 days in wild type 129/sv mice, decreases the formation of micronuclei in bone marrow cells and DNA damage in colon and lung tissues compared to control irradiated mice at sub-lethal and lethal doses, increasing the overall survival fraction by 37% after 10Gy total body irradiation. We next pre-treated with metformin and then exposed 129/sv mice, to a galactic cosmic rays simulation (GCRsim), at the NASA Space Radiation Laboratory (NSRL). We found metformin pre-treatment decreases the presence of bone marrow micronuclei and DNA damage in colon and lung tissues and an increase of 8-oxoguanine DNA glycosylase-1 (OGG1) expression. Our data highlight a radioprotective effect of metformin through an indirect modulation of the gene expression involved in the cellular detoxification rather than its effects on mitochondria. [ABSTRACT FROM AUTHOR]

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33‐beam‐GCR (33‐GCR) show short‐term cognitive deficits but reports on female rodents and long‐term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33‐GCR on female mice? Also, can an antioxidant/anti‐inflammatory compound (CDDO‐EA) mitigate the impact of 33‐GCR? Mature (6‐month‐old) C57BL/6J female mice received CDDO‐EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham‐irradiation (IRR) or whole‐body 33‐GCR (0.75Gy) on the 4th day. Three‐months post‐IRR, mice underwent two touchscreen‐platform tests: (1) location discrimination reversal (tests behavior pattern separation and cognitive flexibility, abilities reliant on the dentate gyrus) and (2) stimulus–response learning/extinction. Mice then underwent arena‐based behavior tests (e.g. open field, 3‐chamber social interaction). At the experiment's end (14.25‐month post‐IRR), an index relevant to neurogenesis was quantified (doublecortin‐immunoreactive [DCX+] dentate gyrus immature neurons). Female mice exposed to Veh/Sham vs. Veh/33‐GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO‐EA/Sham and CDDO‐EA/33‐GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33‐GCR), and CDDO‐EA/33‐GCR mice had better cognitive flexibility (reversal number) vs. Veh/33‐GCR mice. One radiation effect/CDDO‐EA countereffect also emerged: Veh/33‐GCR mice had slower stimulus–response learning (days to completion) vs. all other groups, including CDDO‐EA/33‐GCR mice. In general, all mice showed normal anxiety‐like behavior, exploration, and habituation to novel environments. There was also a change relevant to neurogenesis: Veh/33‐GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission‐relevant cognitive processes and CDDO‐EA is a potential dietary countermeasure for space‐radiation CNS risks. [ABSTRACT FROM AUTHOR]