DMAT

IC50 value: 0.13uM. DMAT also displays submicromolar IC50 values with almost all of the other kinases with special reference to PKD1, PIM3 and PIM1[3]. Protein kinase CK2 is involved in cell proliferation and survival, and found overexpressed in virtually all types of human cancer, including breast cancer. We demonstrate that inhibition of CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT), a potent and specific CK2 inhibitor, results in caspase-mediated killing of human breast cancer cells with acquired resistance to antiestrogens [1]. In vitro:. Treatment with DMAT decreases the secretion of aldosterone, dehydroepiandrosterone sulfate, and androstendione in H295R human adrenocortical cancer cell line and results in an accumulation of 17-OH-progesterone. Cell growth as measured by the MTT and 5-bromo-2'-deoxyuridine incorporation assays is inhibited, and cell cycle analysis has revealed a slight induction of apoptosis[2]. PIM1 is also inhibited by DMAT by a mechanism which is competitive with respect to ATP. However, IC50 determinations at increasing ATP concentration denote weak competition by ATP which, at almost physiological concentration (0.6 mM), causes only a 5.3-fold decrease in DMAT inhibition, as compared with 1 μM ATP concentration, whereas in the same range of ATP concentration the IC50 with CK2 increases 22.1-fold, doubling the value calculated with PIM1 (1.2 μM) [3]. in vivo: Similar to Sorafenib, DMAT interfered with NFκB activation and Wnt-signaling. Of the kinases inhibited by DMAT at almost equimolar IC50, CK2 and PIM-3 were found to be over-expressed or more active in hepatoma cells and human HCC tissue. Knockdown of PIM-3 or CK2 by shRNA revealed that both kinases are important for hepatoma cell proliferation and survival [4]. DMAT, might represent a promising therapeutic approach in future HCC therapy. Clinical trial: Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene[3].

Tenfibgen-DMAT Nanocapsule Delivers CK2 Inhibitor DMAT to Prostate Cancer Xenograft Tumors Causing Inhibition of Cell Proliferation.[Pubmed:25893034]

Mol Cell Pharmacol. 2014;6(2):15-25.

CK2 is a master regulator protein kinase which demonstrates heightened expression in diverse cancer types and is considered a promising target for therapy. Given its ubiquitous expression and potent influence on cell survival, cancer cell-directed targeting of the CK2 signal is an important factor for development of an anti-CK2 therapeutic. We previously reported on the malignant cell specificity and effect on CK2 signaling of a tenfibgen (TBG) based nanocapsule for delivery of the CK2 small molecule inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) in cultured prostate cancer cells. Here we tested the ability of TBG-DMAT to affect the growth of prostate xenograft tumors in mice. Our results show that treatment of PC3-LN4 xenograft tumors with TBG-DMAT caused loss of proliferative Ki-67 signal as well as Nuclear Factor-kappa B (NF-kappaB) expression in the tumors. Further, the TBG-DMAT nanocapsule was detected in tumors and not in liver or testis. In conclusion, TBG-based nanocapsule delivery of anti-CK2 small molecule drugs holds significant promise for treatment of prostate cancer.

[Experience of DMAT rescue activity by doctor-helicopter in Tohoku Area after the earthquake].[Pubmed:22860313]

Masui. 2012 Jul;61(7):771-4.

We operated rescue activities in Tohoku area after the earthquake of March 11th, 2011. From our hospital, a doctor-helicopter flew to the staging care unit at Hanamaki airport with two members of the disaster medical assistance team (DMAT), one of whom was an anesthesiologist. The helicopter carried ten patients by nine flight missions, who were the victims of tsunami after the earthquake. There were seven doctor-helicopters from all over Japan and did the missions based at Hanamaki airport. The missions was quite different from our usual job as an anesthesiologist, but we could transfer the patients safely by using some knowledge of stabilizing the unstable patients as flight doctors. We report the details of our activities by our doctor-helicopters in Tohoku area.

Quinone reductase 2 is an adventitious target of protein kinase CK2 inhibitors TBBz (TBI) and DMAT.[Pubmed:25379648]

Biochemistry. 2015 Jan 13;54(1):47-59.

Quinone reductase 2 (NQO2) exhibits off-target interactions with two protein kinase CK2 inhibitors, 4,5,6,7-1H-tetrabromobenzimidazole (TBBz) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT). TBBz and DMAT induce apoptosis in cells expressing an inhibitor-resistant CK2, suggesting that the interaction with NQO2 may mediate some of their pharmacological effects. In this study, we have fully characterized the binding of TBBz and DMAT to NQO2. Fluorescence titrations showed that TBBz and DMAT bind oxidized NQO2 in the low nanomolar range; in the case of TBBz, the affinity for NQO2 was 40-fold greater than its affinity for CK2. A related CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB), which failed to cause apoptosis in cells expressing inhibitor-resistant CK2, binds NQO2 with an affinity 1000-fold lower than those of TBBz and DMAT. Kinetic analysis indicated that DMAT inhibits NQO2 by binding with similar affinities to the oxidized and reduced forms. Crystal structure analysis showed that DMAT binds reduced NQO2 in a manner different from that in the oxidized state. In oxidized NQO2, TBBz and DMAT are deeply buried in the active site and make direct hydrogen and halogen bonds to the enzyme. In reduced NQO2, DMAT occupies a more peripheral region and hydrogen and halogen bonds with the enzyme are mediated through three water molecules. Therefore, although TBB, TBBz, and DMAT are all potent inhibitors of CK2, they exhibit different activity profiles toward NQO2. We conclude that the active site of NQO2 is fundamentally different from the ATP binding site of CK2 and the inhibition of NQO2 by CK2 inhibitors is adventitious.

Experience from the Great East Japan Earthquake response as the basis for revising the Japanese Disaster Medical Assistance Team (DMAT) training program.[Pubmed:25410400]

Disaster Med Public Health Prep. 2014 Dec;8(6):477-84.

OBJECTIVE: The objective of this study was to draft a new Japanese Disaster Medical Assistance Team (DMAT) training program based on the responses to the Great East Japan Earthquake. METHODS: Working group members of the Japan DMAT Investigative Commission, Ministry of Health, Labour and Welfare, reviewed reports and academic papers on DMAT activities after the disaster and identified items in the current Japanese DMAT training program that should be changed. A new program was proposed that incorporates these changes. RESULTS: New topics that were identified to be added to the DMAT training program were hospital evacuation, preparations to receive DMATs at damaged hospitals, coordination when DMAT activities are prolonged, and safety management and communication when on board small helicopters. The use of wide-area transport was reviewed and changes were made to cover selection of various transport means including helicopter ambulances. Content related to confined space medicine was removed. The time spent on emergency medical information system (EMIS) practical training was increased. Redundant or similar content was combined and reorganized, and a revised DMAT training program that did not increase the overall training time was designed. CONCLUSION: The revised DMAT training program will provide practical training better suited to the present circumstances in Japan.