No abstract

Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (As III ) is also an effective chemotherapeutic agent. The current use of As III in chemotherapy is limited to acute promyelocytic leukemia (APL). However, As III was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPRbased approach to identify modulators of As III toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased As III tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to As III whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to As III . Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to As III . Our data suggest a model in which an intracellular interaction between selenium and As III may impact intracellular As III levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of As III in CML cells. Targeting such processes simultaneously with As III treatment could potentiate As III in CML therapy.

Intestinal mucositis is an important problem in the patients receiving cancer treatment. We aimed to investigate the effect of anakinra, which is a well known anti-oxidant and anti-inflammatory agent, on methotrexateinduced small intestine mucositis in rats. Forty rats were divided into 4 groups with 10 in each group. The healthy group (HG) and the methotrexate group (MTXG) were given distilled water, while the methotrexate + anakinra 50 (MTX+ANA50) and the methotrexate + anakinra 100 (MTX+ANA100) groups were intraperitoneally administered 50 and 100 mg/kg of anakinra. After one hour, the MTXG, MTX+ANA50 and MTX+ANA100 groups were given oral methotrexate at a dose of 5 mg/kg. This procedure was repeated once a day for 7 days. After the rats had been sacrificed, the small intestine tissue of rats were removed for the assesment of biochemical markers, histopathological evaluation and gene expression analyze. Statistical analyses of the data were performed using one-way ANOVA. Malondialdehyde (MDA), myeloperoxidase (MPO) and interleukin-6 (IL-6) levels were significantly higher, whereas total glutathione (tGSH) levels were significantly lower in MTXG (P<0.001) compared to other groups. MTX also increased IL-1β and TNF-α gene expression levels in MTXG (P<0.001). Inflammatory cell infiltration and damage to the villus were observed histopathologically in the MTXG group, whereas only mild inflammation was seen in the MTX+ANA100 group. A dose of 100 mg/kg of anakinra prevented the increase of the biochemical markers and gene expression levels better than a dose of 50 mg/kg. Intestinal mucositis caused by MTX may be preventible by co-administered anakinra.

Although cord hemoglobin and mean corpuscular volume were not affected by maternal anemia, increased cord serum erythropoietin levels related to low maternal hemoglobin levels suggest an induced fetal erythropoiesis in maternal anemia.