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PRIMA-1met

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https://www.readbyqxmd.com/read/27806324/prima-1met-suppresses-colorectal-cancer-independent-of-p53-by-targeting-mek
#1
Tao Lu, Yanmei Zou, Guogang Xu, Jane A Potter, Garry L Taylor, Qiuhong Duan, Qin Yang, Huihua Xiong, Hong Qiu, Dawei Ye, Peng Zhang, Shiying Yu, Xianglin Yuan, Feng Zhu, Yihua Wang, Hua Xiong
PRIMA-1Met is the methylated PRIMA-1 (p53 reactivation and induction of massive apoptosis) and could restore tumor suppressor function of mutant p53 and induce p53 dependent apoptosis in cancer cells harboring mutant p53. However, p53 independent activity of PRIMA-1Met remains elusive. Here we reported that PRIMA-1Met attenuated colorectal cancer cell growth irrespective of p53 status. Kinase profiling revealed that mitogen-activated or extracellular signal-related protein kinase (MEK) might be a potential target of PRIMA-1Met...
October 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27533246/sensitivity-to-prima-1met-is-associated-with-decreased-mgmt-in-human-glioblastoma-cells-and-glioblastoma-stem-cells-irrespective-of-p53-status
#2
Mariia Patyka, Zeinab Sharifi, Kevin Petrecca, Jose Mansure, Bertrand Jean-Claude, Siham Sabri
Alterations of the TP53 tumor suppressor gene occur in ~30% of primary glioblastoma (GBM) with a high frequency of missense mutations associated with the acquisition of oncogenic "gain-of-function" (GOF) mutant (mut)p53 activities. PRIMA-1MET/APR-246, emerged as a promising compound to rescue wild-type (wt)p53 function in different cancer types. Previous studies suggested the role of wtp53 in the negative regulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a major determinant in resistance to therapy in GBM treatment...
August 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27375019/prima-1met-induces-mitochondrial-apoptosis-through-activation-of-caspase-2
#3
J Shen, H Vakifahmetoglu, H Stridh, B Zhivotovsky, K G Wiman
No abstract text is available yet for this article.
July 4, 2016: Oncogene
https://www.readbyqxmd.com/read/27347849/proteasome-machinery-is-instrumental-in-a-common-gain-of-function-program-of-the-p53-missense-mutants-in-cancer
#4
Dawid Walerych, Kamil Lisek, Roberta Sommaggio, Silvano Piazza, Yari Ciani, Emiliano Dalla, Katarzyna Rajkowska, Katarzyna Gaweda-Walerych, Eleonora Ingallina, Claudia Tonelli, Marco J Morelli, Angela Amato, Vincenzo Eterno, Alberto Zambelli, Antonio Rosato, Bruno Amati, Jacek R Wiśniewski, Giannino Del Sal
In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway...
August 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/26986846/prima-1met-induces-apoptosis-through-accumulation-of-intracellular-reactive-oxygen-species-irrespective-of-p53-status-and-chemo-sensitivity-in-epithelial-ovarian-cancer-cells
#5
Nobuhisa Yoshikawa, Hiroaki Kajiyama, Kae Nakamura, Fumi Utsumi, Kaoru Niimi, Hiroko Mitsui, Ryuichiro Sekiya, Shiro Suzuki, Kiyosumi Shibata, David Callen, Fumitaka Kikkawa
There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA‑1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear...
May 2016: Oncology Reports
https://www.readbyqxmd.com/read/26868746/apr-246-prima-1met-inhibits-and-reverses-squamous-metaplasia-in-human-conjunctival-epithelium
#6
Jing Li, Cheng Li, Guoliang Wang, Zhen Liu, Pei Chen, Qichen Yang, Nuo Dong, Huping Wu, Zuguo Liu, Wei Li
PURPOSE: Squamous metaplasia is a common pathologic condition in ocular surface diseases for which there is no therapeutic medication in clinic. In this study, we investigated the effect of a small molecule, APR-246/PRIMA-1(Met), on squamous metaplasia in human conjunctival epithelium. METHODS: Human conjunctival explants were cultured for up to 12 days under airlifting conditions. Epithelial cell differentiation and proliferation were assessed by Cytokeratin 10 (K10), K14, K19, Pax6, MUC5AC, and p63 immunostaining patterns...
February 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/26771839/mirna-29a-as-a-tumor-suppressor-mediates-prima-1met-induced-anti-myeloma-activity-by-targeting-c-myc
#7
Manujendra N Saha, Jahangir Abdi, Yijun Yang, Hong Chang
The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc. The baseline expression of miR-29a was significantly lower in MM cell lines and MM patient samples compared to normal hematopoietic cells...
February 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/26452133/prima-1met-apr-246-inhibits-growth-of-colorectal-cancer-cells-with-different-p53-status-through-distinct-mechanisms
#8
Xiao-Lan Li, Jianbiao Zhou, Zit-Liang Chan, Jing-Yuan Chooi, Zhi-Rong Chen, Wee-Joo Chng
PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1met mediated activity...
November 3, 2015: Oncotarget
https://www.readbyqxmd.com/read/25803193/prima-1met-induces-apoptosis-in-waldenstr%C3%A3-m-s-macroglobulinemia-cells-independent-of-p53
#9
Mona Sobhani, Jahangir Abdi, Saha N Manujendra, Christine Chen, Hong Chang
PRIMA-1Met has shown promising preclinical activity in various cancer types. However, its effect on Waldenström's Macroglobulinemia (WM) cells as well as its exact mechanism of action is still elusive. In this study, we evaluated the anti- tumor activity of PRIMA-1Met alone and in combination with dexamethasone or bortezomib in WM cell lines and primary samples. Treatment of WM cells with PRIMA-1Met resulted in induction of apoptosis, inhibition of migration and suppression of colony formation. Upon PRIMA-1Met treatment, p73 was upregulated and Bcl-xL was down-regulated while no significant change in expression of p53 was observed...
2015: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/25455730/p53-as-a-target-for-the-treatment-of-cancer
#10
REVIEW
Michael J Duffy, Naoise C Synnott, Patricia M McGowan, John Crown, Darran O'Connor, William M Gallagher
TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as ‘‘undruggable’’. This situation has now changed, as several compounds have become available that can restore wild-type properties to mutant p53 (e...
December 2014: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/25006124/prima-1met-induces-myeloma-cell-death-independent-of-p53-by-impairing-the-gsh-ros-balance
#11
Benoît Tessoulin, Géraldine Descamps, Philippe Moreau, Sophie Maïga, Laurence Lodé, Catherine Godon, Séverine Marionneau-Lambot, Thibauld Oullier, Steven Le Gouill, Martine Amiot, Catherine Pellat-Deceunynck
The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1(Met)) in inducing myeloma cell death, using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the lethal dose (LD50) of HMCLs revealed that HMCLs displayed heterogeneous sensitivity, with an LD50 ranging from 4 μM to more than 200 μM. The sensitivity of HMCLs did not correlate with myeloma genomic heterogeneity or TP53 status, and PRIMA-1(Met) did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5...
September 4, 2014: Blood
https://www.readbyqxmd.com/read/24157875/apr-246-prima-1met-inhibits-thioredoxin-reductase-1-and-converts-the-enzyme-to-a-dedicated-nadph-oxidase
#12
X Peng, M-Q-Z Zhang, F Conserva, G Hosny, G Selivanova, V J N Bykov, E S J Arnér, K G Wiman
The low-molecular-weight compound APR-246 (PRIMA-1(MET)) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. APR-246 inhibited both recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting of the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much more efficient TrxR1 inhibitors than APR-246 itself, indicating that MQ is the active compound responsible for TrxR1 enzyme inhibition...
2013: Cell Death & Disease
https://www.readbyqxmd.com/read/24030633/prima-1met-apr-246-displays-high-antitumor-activity-in-multiple-myeloma-by-induction-of-p73-and-noxa
#13
Manujendra N Saha, Hua Jiang, Yijun Yang, Donna Reece, Hong Chang
Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells...
November 2013: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/23355677/impaired-epithelial-differentiation-of-induced-pluripotent-stem-cells-from-ectodermal-dysplasia-related-patients-is-rescued-by-the-small-compound-apr-246-prima-1met
#14
Ruby Shalom-Feuerstein, Laura Serror, Edith Aberdam, Franz-Josef Müller, Hans van Bokhoven, Klas G Wiman, Huiqing Zhou, Daniel Aberdam, Isabelle Petit
Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines...
February 5, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/22965953/targeting-p53-in-vivo-a-first-in-human-study-with-p53-targeting-compound-apr-246-in-refractory-hematologic-malignancies-and-prostate-cancer
#15
COMPARATIVE STUDY
Sören Lehmann, Vladimir J N Bykov, Dina Ali, Ove Andrén, Honar Cherif, Ulf Tidefelt, Bertil Uggla, Jeffrey Yachnin, Gunnar Juliusson, Ali Moshfegh, Christer Paul, Klas G Wiman, Per-Ola Andersson
PURPOSE: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246. PATIENTS AND METHODS: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer...
October 10, 2012: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/21415220/prima-1met-apr-246-induces-apoptosis-and-tumor-growth-delay-in-small-cell-lung-cancer-expressing-mutant-p53
#16
Roza Zandi, Galina Selivanova, Camilla Laulund Christensen, Thomas Alexander Gerds, Berthe Marie Willumsen, Hans Skovgaard Poulsen
PURPOSE: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations...
May 1, 2011: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/21239882/prima-1met-apr-246-induces-wild-type-p53-dependent-suppression-of-malignant-melanoma-tumor-growth-in-3d-culture-and-in-vivo
#17
Wenjie Bao, Ming Chen, Xu Zhao, Ravjiv Kumar, Clemens Spinnler, Minna Thullberg, Natalia Issaeva, Galina Selivanova, Staffan Strömblad
Disseminating malignant melanoma is a lethal disease highly resistant to radio- and chemotherapy. Therefore, the development of new treatment strategies is strongly needed. Tumor suppressor p53-mediated apoptosis is essential for the response to radio- and chemotherapy. Although p53 is not frequently mutated in melanoma, it is inactivated by integrin αv-mediated signaling, as we previously demonstrated 1, which may account, at least partially, for increased apoptosis resistance of malignant melanoma. In this study we addressed the question whether functional restoration of p53 by APR-246 (PRIMA-1Met), which can reactivate mutant p53 and induce massive apoptosis in cancer cells, is able to restore the function of inactive p53 in melanoma...
January 15, 2011: Cell Cycle
https://www.readbyqxmd.com/read/20946886/prima-1-cytotoxicity-correlates-with-nucleolar-localization-and-degradation-of-mutant-p53-in-breast-cancer-cells
#18
Debora Russo, Laura Ottaggio, Ilaria Penna, Giorgia Foggetti, Gilberto Fronza, Alberto Inga, Paola Menichini
PRIMA-1 has been identified as a compound that restores the transactivation function to mutant p53 and induces apoptosis in cells expressing mutant p53. Studies on subcellular distribution of the mutant p53 protein upon treatment with PRIMA-1Met, a methylated form of PRIMA-1, have suggested that redistribution of mutant p53 to nucleoli may play a role in PRIMA-1 induced apoptosis. Here, we specifically investigated the influence of PRIMA-1 on cellular localization of mutated p53-R280K endogenously expressed in tumour cells...
November 12, 2010: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/19946333/mutant-p53-reactivation-by-prima-1met-induces-multiple-signaling-pathways-converging-on-apoptosis
#19
J M R Lambert, A Moshfegh, P Hainaut, K G Wiman, V J N Bykov
The low molecular weight compound PRIMA-1(MET) reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1(MET) on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1(MET) affected transcription of a significantly larger number of genes in the mutant p53-expressing cells compared to the p53 null cells. Genes affected by PRIMA-1(MET) in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3gamma and the pro-apoptotic Noxa...
March 4, 2010: Oncogene
https://www.readbyqxmd.com/read/19323829/prima-1met-induces-nucleolar-translocation-of-epstein-barr-virus-encoded-ebna-5-protein
#20
György Stuber, Emilie Flaberg, Gabor Petranyi, Rita Otvös, Nina Rökaeus, Elena Kashuba, Klas G Wiman, George Klein, Laszlo Szekely
The low molecular weight compound, PRIMA-1MET restores the transcriptional transactivation function of certain p53 mutants in tumor cells. We have previously shown that PRIMA-1MET induces nucleolar translocation of p53, PML, CBP and Hsp70. The Epstein-Barr virus encoded, latency associated antigen EBNA-5 (also known as EBNA-LP) is required for the efficient transformation of human B lymphocytes by EBV. EBNA-5 associates with p53-hMDM2-p14ARF complexes. EBNA-5 is a nuclear protein that translocates to the nucleolus upon heat shock or inhibition of proteasomes along with p53, hMDM2, Hsp70, PML and proteasome subunits...
2009: Molecular Cancer
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