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1.
Commun Biol ; 5(1): 571, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681099

RESUMO

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Ribonucleotídeo Redutases , Animais , Antineoplásicos/farmacologia , Replicação do DNA , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas Nucleares/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores
2.
Cancer Sci ; 112(1): 422-432, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33140501

RESUMO

Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.


Assuntos
Reparo do DNA/efeitos dos fármacos , Floxuridina/farmacologia , Pirimidinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Galinhas , Dano ao DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Timidilato Sintase/antagonistas & inibidores
3.
Chem Pharm Bull (Tokyo) ; 68(2): 155-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009083

RESUMO

Combination tablets containing multiple active pharmaceutical ingredients (APIs) are expected to improve patient convenience by decreasing the number of tablets to be taken; thus, numerous formulations containing multiple APIs have recently been developed. To allow for dose adjustments based on patient conditions, many tablets have a bisection line to allow equal division of tablets. However, there have been no investigations regarding content uniformity among divided combination tablets. Therefore, in this study, the content uniformity of combination tablets after division was investigated using near IR and low-frequency (LF) Raman spectroscopy imaging as well as the Japanese Pharmacopoeia (JP) content uniformity tests. As model drugs, five tablets of three combination drugs containing 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) and benserazide hydrochloride (BNS) as APIs for treating Parkinson's disease were bisected; the resultant 10 samples were subjected to the JP content uniformity tests. We found that acceptance values of L-DOPA and BNS were 11.0-21.9% and 13.3-17.5%, respectively, with some non-conformity to the maximum allowed acceptance value (15.0%) as per the current JP. Image analyses by near IR showed that L-DOPA, BNS, lactose, and corn starch were uniformly distributed in each tablet; moreover, LF Raman spectroscopy imaging also supported the result that L-DOPA, BNS, and lactose were evenly distributed. Therefore, drug content in the tablets was uniform; thus, careful manipulation was recommended in the tablet bisection. However, the results of bisection line specifications and hardness tests revealed that the ease of division differed depending on the tablets, which warrants attention.


Assuntos
Antiparkinsonianos/análise , Benserazida/análise , Levodopa/análise , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Análise Espectral Raman/métodos , Combinação de Medicamentos , Comprimidos
4.
Chem Pharm Bull (Tokyo) ; 67(9): 929-934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474731

RESUMO

We investigated the water contents in commercial semi-solid preparations used for pressure ulcer (PU) treatment using near-IR spectroscopy (NIRS) and compared the results with those measured using the Karl Fischer (KF) method. The aim of this study was to determine a standard method and select the appropriate topical preparation with the optimal moisture for PU treatment. The water absorption properties of bases and formulations were evaluated with a time-dependent factor using Transwell as the model membrane. KF and NIRS were applicable as measurement methods of the water content in semi-solid formulations. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. The water absorption characteristics tested using Transwell revealed that the rate of and capacity for water absorption are determined not only by the absorption ability of the polymer base but also by other factors, such as the osmotic pressure exerted by additives. KF and NIR measurements can be used to choose external skin preparations to control the amount of water in PU treatment.


Assuntos
Composição de Medicamentos/métodos , Água/química , Administração Tópica , Glicerol/química , Humanos , Pomadas/química , Pomadas/uso terapêutico , Polietilenoglicóis/química , Úlcera por Pressão/tratamento farmacológico , Espectroscopia de Luz Próxima ao Infravermelho
5.
Cancer Sci ; 105(5): 553-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24597654

RESUMO

Bone metastasis is a multistep process that includes cancer cell dissemination, colonization, and metastatic growth. Furthermore, this process involves complex, reciprocal interactions between cancer cells and the bone microenvironment. Bone resorption is known to be involved in both osteolytic and osteoblastic bone metastasis. However, the precise roles of the bone resorption in the multistep process of osteoblastic bone metastasis remain unidentified. In this study, we show that bone resorption plays important roles in cancer cell colonization during the initial stage of osteoblastic bone metastasis. We applied bioluminescence/X-ray computed tomography multimodal imaging that allows us to spatiotemporally analyze metastasized cancer cells and bone status in osteoblastic bone metastasis models. We found that treatment with receptor activator of factor-κB ligand (RANKL) increased osteoblastic bone metastasis when given at the same time as intracardiac injection of cancer cells, but failed to increase metastasis when given 4 days after cancer cell injection, suggesting that RANKL-induced bone resorption facilitates growth of cancer cells colonized in the bone. We show that insulin-like growth factor-1 released from the bone during bone resorption and hypoxia-inducible factor activity in cancer cells cooperatively promoted survival and proliferation of cancer cells in bone marrow. These results suggest a mechanism that bone resorption and hypoxic stress in the bone microenvironment cooperatively play an important role in establishing osteoblastic metastasis.


Assuntos
Neoplasias Ósseas/secundário , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Fator 1 Induzível por Hipóxia/metabolismo , Osteossarcoma/secundário , Ligante RANK/farmacologia , Somatomedinas/metabolismo , Animais , Células da Medula Óssea/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Ativação Enzimática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fator de Crescimento Transformador beta/metabolismo , Transplante Heterólogo , Microambiente Tumoral
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