Indiana University-Purdue University Indianapolis (IUPUI) / Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with a dismal prognosis. Targeted therapies for breast cancer with expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are currently available; however, due to the lack of ER, PR, and HER2 in TNBC, targeted therapies are limited. While surgery and traditional chemotherapy remain the standard of care, development of a new treatment strategy for TNBC is needed to improve clinical outcomes. Fatty acid synthase (FASN) has been implicated as a metabolic oncogene and has given cancer cells a survival advantage by increasing NHEJ repair. Recently, it has been shown that FDA-approved proton pump inhibitors, used for the treatment of acid related digestive diseases, have antitumor effects. Here, I show that a metabolite of lansoprazole, 5-hydroxy lansoprazole sulfide, has increased potency over parent compound lansoprazole. 5-hydroxy lansoprazole sulfide inhibits FASN, leading to a decrease in PARP and NHEJ DNA repair activity in TNBC. Ultimately, this leads to an increase in DNA damage and cell death via apoptosis. These findings suggest that 5-hydroxy lansoprazole sulfide, as a metabolite of lansoprazole, may have better activity in suppressing TNBC cells and that 5-hydroxy lansoprazole sulfide may be developed as a therapeutic for TNBC treatment. Furthermore, due to the role of FASN in increasing NHEJ repair, we hypothesized that FASN played a role in resistance to CC-115, a dual mTOR/DNA-PK inhibitor currently in clinical trials, by increasing DNA-PK activity. However, it was found that ABCG2, an ATP-binding cassette transporter, and not FASN, has a role in CC-115 resistance. ABCG2 effluxes CC-115 from cancer cells, increasing resistance to treatment. Inhibition of ABCG2 by FTC or PZ39C8 led to accumulation of CC-115 within cells and sensitization to treatment. Therefore, ABCG2 status should be assessed to stratify patients into treatment groups, increasing the efficacy of CC-115 treatment. / 2020-02-21

共著者あり。共著者名:Asaka Masahiro, Kudo Mineo, Sukegawa Makoto, Katagiri Masaki, Koshiyama Tatsumi, Kagaya Hidetoshi, Nishikawa Keiko, Hokari Kaku, Takeda Hiroshi, Sugiyama Toshiro. / Hokkaido University (北海道大学) / 博士 / 医学

Submitted by Geyciane Santos (geyciane_thamires@hotmail.com) on 2015-12-02T20:20:33Z No. of bitstreams: 1 Dissertação - Arlesson Freire de Lima.pdf: 1069637 bytes, checksum: 3aea5b6e8da4bd59f2332f51e3fc7ece (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-12-03T17:56:35Z (GMT) No. of bitstreams: 1 Dissertação - Arlesson Freire de Lima.pdf: 1069637 bytes, checksum: 3aea5b6e8da4bd59f2332f51e3fc7ece (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-12-03T18:14:35Z (GMT) No. of bitstreams: 1 Dissertação - Arlesson Freire de Lima.pdf: 1069637 bytes, checksum: 3aea5b6e8da4bd59f2332f51e3fc7ece (MD5) / Made available in DSpace on 2015-12-03T18:14:35Z (GMT). No. of bitstreams: 1 Dissertação - Arlesson Freire de Lima.pdf: 1069637 bytes, checksum: 3aea5b6e8da4bd59f2332f51e3fc7ece (MD5) Previous issue date: 2015-07-31 / Não informada / In this paper, we propose the determination of lansoprazole content, selective inhibitor of H + / K + -ATPase gastric using titration based on digital image (Digital Image-Based Titration). The DIB system uses a webcam to acquisition of digital images based on the color system RGB (Red-Green-Blue). During the titration procedure the method was applied to the acid-base titration of the drug lansoprazole with hydrochloric acid. The titration was performed by the DIB, and by potentiometry. In DIB methodology for each volume of titrant added an image was captured and manipulated to obtaining the standard values (N=√R̅2+G̅2+B̅2). The spent volume of titrant to reach the equivalence point was obtained from the second derivative of the titration curve. The results of the samples showed no statistically significant differences at the 95% confidence level was observed after applying the paired t test (tcalculado = 0,439 e tcrítico = 2,353). The relative standard deviations using the DIB methodology with the exception of Sample C, was below 1.0%. / Neste trabalho, propõe-se a determinação do teor de lansoprazol, agente inibidor seletivo da H+/K+-ATPase gástrica, utilizando titulação baseada em imagem digital (Digital Image-Based Titration). O sistema DIB utiliza uma webcam para aquisição das imagens digitais com base no sistema de cor RGB (Red-Green-Blue). Durante o procedimento de titulação o método foi aplicado na titulação ácido-base do fármaco lansoprazol com o ácido clorídrico. A titulação foi realizada por DIB e por potenciometria. Na metodologia DIB para cada volume do titulante adicionado uma imagem era capturada e manipulada para obtenção dos valores da norma (N=√R̅2+G̅2+B̅2). O volume gasto de titulante para atingir o ponto de equivalência, foi obtido a partir da segunda derivada da curva de titulação. Os resultados obtidos das amostras não apresentaram nenhuma diferença estatística significativa no nível de confiança de 95 % que foi verificada após aplicar o teste t emparelhado (tcalculado = 0,439 e tcrítico = 2,353). Os desvios padrão relativos utilizando a metodologia DIB, com exceção da amostra C, ficaram abaixo de 1,0 %.

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An LC-MS/MS method was developed and validated to be used as a stability indicating assay for the study of a 3 mg/mL lansoprazole oral suspension. The method utilizes a UPLC (ultra-performance liquid chromatography) column and unique mass spectrometric detection (ion-trap time-of-flight (IT-TOF)) to achieve a sensitive (LOD 2 ng/mL), accurate, and reproducible quantification of lansoprazole. This method reports an intraday and interday coefficient of variation of 2.98 ± 2.17% ( for each concentration for each day) and 3.07 ± 0.89% ( for each concentration), respectively. Calibration curves (5–25 μg/mL) were found to be linear with an value ranging from 0.9972 to 0.9991 on 4 different days. Accuracy of the assay, expressed as % error, ranged from 0.30 to 5.22%. This method is useful for monitoring the stability of lansoprazole in oral suspension.

OBJECTIVE The purpose of this study was to examine the stability of a generic lansoprazole product in a 3 mg/mL sodium bicarbonate suspension under room temperature and refrigerated conditions. METHODS Lansoprazole suspensions (3 mg/mL) were prepared in triplicate using an 8.4% sodium bicarbonate vehicle for each storage condition (room temperature and refrigerated). During 1 month, samples from each replicate were periodically removed and analyzed for lansoprazole concentration by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Each sample was spiked with 10 mg/L omeprazole to serve as the internal standard. A positive electrospray LC-MS/MS method was validated over the calibration range of 5 to 25 mg/L using Food and Drug Administration Guidance. The identities of the analyte and internal standard in the samples were verified by monitoring the MS/MS transitions of m/z 370 to m/z 252 and m/z 346 to m/z 198 for lansoprazole and omeprazole, respectively. Additionally, the pH of the suspensions was monitored throughout the study. RESULTS The stability of lansoprazole in the oral sodium bicarbonate suspension under refrigeration is compromised prior to what has been previously reported in the literature. Samples kept at room temperature lost >10% of the lansoprazole after 48 hours compared with the refrigerated samples, which maintained integrity up to 7 days. No statistically significant difference was found between the pH of the room temperature and refrigerated suspension samples, indicating that this factor is not the cause for the differences in stability at these two conditions. CONCLUSIONS This study suggests that the extemporaneously compounded lansoprazole oral suspension prepared in 8.4% sodium bicarbonate should not be stored in plastic oral syringes longer than 48 hours at room temperature and no longer than 7 days when refrigerated. These data indicate an expiration time earlier than that previously reported for the refrigerated product (14 days).