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May 2018: Molecular Cancer Therapeutics
Christophe Deben, Vanessa Deschoolmeester, Jorrit De Waele, Julie Jacobs, Jolien Van den Bossche, An Wouters, Marc Peeters, Christian Rolfo, Evelien Smits, Filip Lardon, Patrick Pauwels
The compound APR-246 (PRIMA-1MET ) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance...
April 21, 2018: Cancers
Qiang Zhang, Vladimir J N Bykov, Klas G Wiman, Joanna Zawacka-Pankau
The TP53 tumor suppressor gene is frequently inactivated in human tumors by missense mutations in the DNA binding domain. TP53 mutations lead to protein unfolding, decreased thermostability and loss of DNA binding and transcription factor function. Pharmacological targeting of mutant p53 to restore its tumor suppressor function is a promising strategy for cancer therapy. The mutant p53 reactivating compound APR-246 (PRIMA-1Met ) has been successfully tested in a phase I/IIa clinical trial. APR-246 is converted to the reactive electrophile methylene quinuclidinone (MQ), which binds covalently to p53 core domain...
April 18, 2018: Cell Death & Disease
Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Konomi Mizuguchi, Mikumi Endo, Ituro Inoue, Koichi Sato, Takehiko Yokomizo
Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1...
2018: Disease Markers
Zongjuan Li, Xiangdong Xu, Yizhuo Li, Kun Zou, Zhuo Zhang, Xiaoying Xu, Yina Liao, Xinrui Zhao, Wei Jiang, Wendan Yu, Wei Guo, Yiming Chen, Yixin Li, Miao Chen, Wu-Guo Deng, Liren Li, Lijuan Zou
BACKGROUND/AIMS: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells...
2018: Cellular Physiology and Biochemistry
Zhi-Xian Yin, Wei Hang, Gang Liu, Yi-Shu Wang, Xiang-Feng Shen, Qian-Hui Sun, Dong-Dong Li, Yong-Ping Jian, Yang-He Zhang, Cheng-Shi Quan, Qinghua Zeng, Yu-Lin Li, Rui-Xun Zhao, Qiang Ding, Zhi-Xiang Xu
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53...
January 5, 2018: Oncotarget
Wei Hang, Zhi-Xian Yin, Gang Liu, Qinghua Zeng, Xiang-Feng Shen, Qian-Hui Sun, Dong-Dong Li, Yong-Ping Jian, Yang-He Zhang, Yi-Shu Wang, Cheng-Shi Quan, Rui-Xun Zhao, Yu-Lin Li, Zhi-Xiang Xu
TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53...
January 18, 2018: Oncogene
Anne Perdrix, Ahmad Najem, Sven Saussez, Ahmad Awada, Fabrice Journe, Ghanem Ghanem, Mohammad Krayem
p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress...
December 16, 2017: Cancers
Kamil Lisek, Dawid Walerych, Giannino Del Sal
The proteasome machinery is a common target of gain-of-function p53 missense mutants. Upregulation of the proteasome fosters chemoresistance to proteasome inhibitors. In triple negative breast cancer cells this resistance mechanism, namely the Nrf2-regulated "bounce-back" response to proteasome inhibitors, can be overcome by targeting p53 mutant proteins with APR-246/PRIMA-1Met.
2017: Molecular & Cellular Oncology
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...
December 13, 2016: Oncotarget
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...
September 13, 2016: Oncotarget
J Shen, H Vakifahmetoglu, H Stridh, B Zhivotovsky, K G Wiman
No abstract text is available yet for this article.
December 15, 2016: Oncogene
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
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
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
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
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
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
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
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
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