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We have developed a novel naphthalimide-based Cd2+ fluorescent probe ( 1), featuring almost no background response, high sensitivity and selectivity toward Cd2+ through its high association constant [ K=(2.10±0.423)×106], and a practical working pH range. Membrane-permeability was conferred on 1 by replacing the imide and amide substituents with n-butyl groups, and hence the derivative ( 4) has found practical utility on fluorescent imaging of Cd2+ in HeLa cells. Comparison of fluorescent properties between various compounds derived from 1 has demonstrated that the carbamoylmethyl groups in 1 function not only as Cd2+ chelators but also as promoters for photoinduced electron transfer (PET) by lowering the basicity of the two tertiary amino groups. As a result, 1 and 4 exhibited highly practical performance as Cd2+ probes under neutral conditions. [ABSTRACT FROM AUTHOR]

Background/aim: Glioblastoma is an incurable cancer with limited treatment options and a low survival rate. Temozolomide is the standard marketed small-molecule agent for glioblastoma therapy; therefore, we aimed to find new drugs among the marketed medicines for brain diseases because of their cerebral migratory property and found lomerizine, used for the treatment of migraine., Materials and Methods: We evaluated the effect of lomerizine and its metabolites against U251 glioblastoma cells and temozolomide-resistant cells, T98G and GB-1, caused by the expression of O(6)-methylguanine-DNA methyltransferase or P-glycoprotein, compared with temozolomide, and combined with it. The mechanism of action was investigated using inhibitors of necrosis or apoptosis., Results: Lomerizine and its metabolite (M6) inhibited the proliferation of glioblastoma cells with greater potency and efficacy than temozolomide, including against temozolomide-resistant cells. The effects of lomerizine and M6 on glioblastoma were mainly attributed to the inhibition of proliferation because cells were not rescued by cell death inhibitors, such as necrosis or apoptosis inhibitors, although they were slightly rescued by necrostatin-1. Additionally, lomerizine and M6 combined with temozolomide were more effective at inhibiting the proliferation of U251 and GB-1 cells at some doses than single treatments., Conclusion: Lomerizine has been used for migraine treatment because of its brain-penetrating properties without serious side-effects; thus, it might potentially be expected to be used alone for glioblastoma, including temozolomide-resistant glioblastoma, or in combination with temozolomide., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The inhibitory activities of docetaxel at a wide range of doses (0.1-10 mg/kg; subcutaneously (s.c.), once/week) in nude mice bearing a human prostate cancer cell (DU145), xenograft model with implantation of DU145 cells or a DU145 solid tumor were examined. This systematic trial demonstrated that (i) docetaxel was more effective in the xenograft model formed by implantation of DU145 cells than in the solid DU145 tumor; (ii) administration of 2.5 mg/kg docetaxel was the critical dose because inhibitory activities were not observed at 2.5 mg/kg, while they were noted at 5 mg/kg and 10 mg/kg in both implantation approaches; (iii) edema-like effects (plump body shape and legs) were observed in both groups at 2.5 mg/kg and the tumor sizes, often increased by blood plasma and other fluids, as well as body weights were higher than at other doses; and (iv) suppression of body weight gain was observed at 10 mg/kg docetaxel., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We have developed a novel naphthalimide-based Cd(2+) fluorescent probe (1), featuring almost no background response, high sensitivity and selectivity toward Cd(2+) through its high association constant [K=(2.10±0.423)×10(6) ], and a practical working pH range. Membrane-permeability was conferred on 1 by replacing the imide and amide substituents with n-butyl groups, and hence the derivative (4) has found practical utility on fluorescent imaging of Cd(2+) in HeLa cells. Comparison of fluorescent properties between various compounds derived from 1 has demonstrated that the carbamoylmethyl groups in 1 function not only as Cd(2+) chelators but also as promoters for photoinduced electron transfer (PET) by lowering the basicity of the two tertiary amino groups. As a result, 1 and 4 exhibited highly practical performance as Cd(2+) probes under neutral conditions., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 ( 1: ), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt ( 2: ) for further studies in vivo. Next, we compared the pharmacokinetics of 1: and 2: via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2: increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Effect of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (FK614), a novel nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) gamma agonist, on glucose tolerance and insulin resistance in peripheral tissues and in liver using Zucker fatty rats (genetically obese and insulin-resistant) was evaluated and compared to other insulin sensitizers. FK614 (0.32, 1 and 3.2 mg/kg), two thiazolidinedione PPAR gamma agonists, rosiglitazone (0.1, 0.32, 1 and 3.2 mg/kg) and pioglitazone (1, 3.2 and 10 mg/kg), and a biguanide, metformin (320 and 1000 mg/kg), were orally administered to Zucker fatty rats once a day for 14 days. Zucker fatty rats treated with FK614 and rosiglitazone were subjected to evaluation by oral glucose tolerance test. Ameliorating effect of each compound on peripheral and hepatic insulin resistance was evaluated using a euglycemic-hyperinsulineamic clamp procedure. FK614 and rosiglitazone dose-dependently improved impaired glucose tolerance in Zucker fatty rats. In addition, FK614 dose-dependently ameliorated peripheral and hepatic insulin resistance in Zucker fatty rats, with the degree of its effect in peripheral tissues almost equivalent to that in liver when compared at each dose tested. Similar data indicating ameliorating effects on insulin resistance was obtained for rosiglitazone and pioglitazone. Metformin showed less potent effects than other insulin sensitizers and its effect in liver tended to be greater than that in peripheral tissues. These findings suggest clinical potential for FK614 as a treatment of type 2 diabetes, acting by ameliorating insulin resistance both in peripheral tissues and liver.