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Moinuddin F.M.,Kagoshima University | Shinsato Y.,Kagoshima University | Komatsu M.,Kagoshima University | Mitsuo R.,Kagoshima University | And 7 more authors.
Oncotarget | Year: 2016

We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP-ATP7B mainly colocalized with doxorubicin. ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0-and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype. Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly. We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration. Source


Inoue A.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Inoue A.,Nagoya University | Arima A.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Kato H.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Ebihara S.,Nagoya University
Congenital Anomalies | Year: 2014

A new type of learning and memory test using a finger maze was conducted in infant cynomolgus monkeys that were exposed to thiamazole (2 and 3.5mg/kg per day to pregnant animals orally) during the fetal period (gestational days 120 to 150). We modified Tsuchida's original finger maze test method by reducing the number of trials per day and simplifying the criteria for achievement of training, and we added a long-term memory test. In the memory test, thiamazole-exposed infants required greater time to complete the finger maze test than the control infants although no effect was noted in the training or learning test. The results suggest that an impaired long-term memory could be detected by our modified finger maze test. © 2014 Japanese Teratology Society. Source


Inoue A.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Inoue A.,Nagoya University | Arima A.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Kato H.,Shin Nippon Biomedical Laboratories SNBL Ltd. | And 4 more authors.
Congenital Anomalies | Year: 2013

Thiamazole, an anti-hyperthyroidism agent, was administered orally to pregnant cynomolgus monkeys at doses of 2.0 and 3.5mg/kg per day from GD 120 to GD 150 to investigate effects on behavioral development of their infants. Swelling of the throat region due to enlargement of the thyroid glands was observed at birth in thiamazole-treated infants, and it returned to normal around postnatal day (PND) 30. At necropsy of infants at 12 months of age, thyroidal weight in the thiamazole groups was increased. This finding suggested the likelihood that administration of thiamazole to maternal animals during the late gestational period induced thyroid goiter in fetal/infant monkeys through placental transfer of thiamazole. No clear changes were noted in thyroid histopathology or serum thyroid hormone levels in maternal animals or infants, but goiter formation might have been indicative of exposure to high thyroid stimulating hormone (TSH) and low T3 or T4in utero from maternal treatment with thiamazole. Age-related changes were observed in the control in behavioral development tests, while infants at 3.5mg/kg showed no age-related decrease in contact behavior and no increase in exploratory activity on PND 90 or PND 170. In addition, the number of eye contacts between PND 210 and PND 240 was less frequent. This indicated that maternal exposure to thiamazole induced mental retardation-like behaviors in infants. Thiamazole may directly inhibit thyroid hormone synthesis in the fetus by placental transfer. From these results, it was speculated that oral administration of thiamazole to maternal animals during the late gestational period induced retardation of behavioral development in their infants. © 2013 Japanese Teratology Society. Source


Kato H.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Dokai M.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Katagiri R.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Arima A.,Shin Nippon Biomedical Laboratories SNBL Ltd. | Ooshima Y.,Shin Nippon Biomedical Laboratories SNBL Ltd.
Congenital Anomalies | Year: 2013

Japan Association for Laboratory Animal Medicine (JALAM) recommends humane handling of rat fetuses. However, it is a challenge to accept proposed euthanizing methods such as cervical dislocation, decapitation and/or intracardiac injection of potassium chloride, because these methods would damage fetal specimens for skeletal and visceral examinations in developmental toxicity studies. The present study aimed at seeking better methodologies for fetal euthanasia and anesthesia. We were unable to accomplish fetal euthanasia directly, but instead, we could euthanize fetuses under pain-controlled anesthesia. It is recommended that hypothermia by immersion in cold physiological saline is an appropriate method for anesthesia. Moreover, we recommend that the anesthetized fetuses should be euthanized immediately by removal of the vital organs or immersion in appropriate fixatives. © 2012 Japanese Teratology Society. Source

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