Abstract:
BACKGROUND:Mutations that activate the PI3K/AKT/mTOR pathway are relatively common in urothelial (bladder) cancers, but how these pathway mutations affect AKT dependency is not known. We characterized the relationship between AKT pathway mutational status and sensitivity to the effects of the selective AKT kinase inhibitor AZ7328 using a panel of 12 well-characterized human bladder cancer cell lines. METHODS:Sequenome DNA sequencing was performed to identify mutations in a panel of 12 urothelial cancer cell lines. Drug-induced proliferative inhibition and apoptosis were quantified using MTT assays and propidium iodide staining with FACS analyses. Protein activation via phosphorylation was measured by immunoblotting. Autophagy was measured by LC3 immunofluorescence and immunoblotting. RESULTS:AZ7328 inhibited proliferation and AKT substrate phosphorylation in a concentration-dependent manner but had minimal effects on apoptosis. Proliferative inhibition correlated loosely with the presence of activating PIK3CA mutations and was strengthened in combination with the mTOR inhibitor rapamycin. AZ7328 induced autophagy in some of the lines, and in the cells exposed to a combination of AZ7328 and chemical autophagy inhibitors apoptosis was induced. CONCLUSIONS:The cytostatic effects of AZ7328 correlate with PIK3CA mutations and are greatly enhanced by dual pathway inhibition using an mTOR inhibitor. Furthermore, AZ7328 can interact with autophagy inhibitors to induce apoptosis in some cell lines. Overall, our results support the further evaluation of combinations of PI3K/AKT/mTOR pathway and autophagy inhibitors in pre-clinical in vivo models and ultimately in patients with PIK3CA mutant bladder cancers.
journal_name
Cancer Biol Therjournal_title
Cancer biology & therapyauthors
Dickstein RJ,Nitti G,Dinney CP,Davies BR,Kamat AM,McConkey DJdoi
10.4161/cbt.21793subject
Has Abstractpub_date
2012-11-01 00:00:00pages
1325-38issue
13eissn
1538-4047issn
1555-8576pii
21793journal_volume
13pub_type
杂志文章abstract:OBJECTIVES:Due to the absence of reliable and accurate biomarkers for the early detection of liver malignancy, circulating microRNAs have recently emerged as great candidates for prompt cancer identification. Therefore, the aim of this study was to investigate the potential of liver-specific circulating microRNAs as an...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2018.1423922
更新日期:2018-05-04 00:00:00
abstract::Antitumor imidazoacridinone C-1311 is a DNA-reactive topoisomerase II and FLT3 receptor tyrosine kinase inhibitor. Here, we demonstrate the mechanism of C-1311 inhibitory action on novel targets: hypoxia-inducible factor-1α (HIF-1α), vascular-endothelial growth factor (VEGF), and angiogenesis. In a cell-free system, C...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.12.7.15980
更新日期:2011-10-01 00:00:00
abstract::The molecular regulation of growth and progression of hormone refractory breast and prostate cancers remains challenging. The Division of Cancer Biology, NCI organized a small "think tank" style workshop and invited scientists in relevant areas to assess the state of science on the biology of hormone refractory tumors...
journal_title:Cancer biology & therapy
pub_type:
doi:10.4161/cbt.8.21.9918
更新日期:2009-11-01 00:00:00
abstract::Discovering drugs has never been an easy task. Traditionally, this task has exclusively been undertaken by large pharmaceutical companies that recovered their high research and development costs by selling expensive medications. Despite the huge amount of time and effort devoted towards drug discovery over the last de...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.2.4.448
更新日期:2003-07-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
abstract::Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The carcinogenesis of colon cancer has been associated with both genetics and environmental factors. It has been found that several signal pathways, includin...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
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更新日期:2009-07-01 00:00:00
abstract::Hepatocellular carcinoma (HCC) is a major health problem worldwide, involving more than 620,000 new cases yearly, with chronic HBV and HCV infection being the most common causes. Because most patients are diagnosed in an advanced state which is usually not amenable to curative therapy, prevention should be the main fo...
journal_title:Cancer biology & therapy
pub_type: 评论,杂志文章
doi:10.4161/cbt.5.12.3737
更新日期:2006-12-01 00:00:00
abstract::Breast cancer is one of the most commonly diagnosed malignancies in women. Despite the remarkable success of mammography screening and use of adjuvant systemic therapy, it is estimated that approximately 200,000 new diagnoses will be made this year and 40,000 deaths will occur due to this disease (American Cancer Soci...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.12.9.17677
更新日期:2011-11-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.6.1.3553
更新日期:2007-01-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.6.2.3628
更新日期:2007-02-01 00:00:00
abstract::AMPK has been termed the fuel sensor of mammalian cells because it directly responds to the depletion of the fuel molecule ATP. In previous work, we found that AMPK is strongly activated by tumor-like hypoxia and glucose deprivation, independently of the oxygen response system associated with HIF-1. We also observed h...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.10.1.12162
更新日期:2010-07-01 00:00:00
abstract::With the increasing interest in development of cytostatic anticancer drugs, the randomized discontinuation trial (RDT) design has been proved to be useful in the evaluation of their clinical activity. In the June 1, 2006 issue of the Journal of Clinical Oncology, a study by Ratain et al. uses RDT in a phase-II placebo...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,随机对照试验
doi:10.4161/cbt.5.10.3290
更新日期:2006-10-01 00:00:00
abstract::Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated intracellular transcription factors, members of the nuclear hormone receptor superfamily. The PPAR subfamily consist of three subtypes encoded by distinct genes denoted PPARalpha, PPARbeta/delta, and PPARgamma. The peroxisome proliferator-activat...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.8.7.7853
更新日期:2009-04-01 00:00:00
abstract::Hypoxia is an important phenomenon in the tumor microenvironment. Hypoxic tumors are more aggressive and resistant to anti-neoplastic treatments. HIF-1alpha plays a major role in the response of tumors to hypoxia, and it is mainly responsible for the "angiogenic switch". HIF-1alpha contributes to tumor aggressiveness,...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.4.10.2195
更新日期:2005-10-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.5.12.3378
更新日期:2006-12-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2019.1647054
更新日期:2019-01-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.6.11.5167
更新日期:2007-11-01 00:00:00
abstract::Invariant natural killer T (iNKT) cells are a distinct subset of human T cells, which expresses an invariant T cell receptor Vα24 Jα18 and recognizes glycolipid antigens in the context of CD1d molecules. iNKT cells exert pivotal regulatory roles in many immune responses, including antitumor immune responses. Alteratio...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.20553
更新日期:2012-07-01 00:00:00
abstract::Mortality data by geographic area and trend-based surveillance are particularly relevant in orienting public health decisions targeting specific populations. We analyzed overall and site-specific cancer mortality between 1988 and 2009 in the metropolitan area of Naples and Caserta in southern Italy. Age-standardized m...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.26425
更新日期:2013-12-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.6.11.4852
更新日期:2007-11-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2006-11-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.7.8.6264
更新日期:2008-08-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.11.1.13878
更新日期:2011-01-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.6.1.3672
更新日期:2007-01-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.27144
更新日期:2014-01-01 00:00:00
abstract::In leukemias, the monitoring techniques on the response after the treatment have clinical importance for evaluating new therapeutic approaches and identifying the risk of relapse. In this study, genetic changes before and after chemotherapy in interphase and metaphase nuclei of bone morrow of adults with provisional d...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.3.9.1039
更新日期:2004-09-01 00:00:00
abstract::Understanding molecular mechanisms involved in melanoma resistance to drugs is a big challenge. Experimental evidences suggested a correlation between mutational status in B-RAF and melanoma cell susceptibility to drugs, such as paclitaxel, doxorubicin and temozolomide, which generate an accumulation of hydrogen perox...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2015.1030546
更新日期:2015-01-01 00:00:00
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journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.4.9.1968
更新日期:2005-09-01 00:00:00
abstract::Ovarian cancer (OC) is xenogeneic that is influenced by many generated factors related to epigenetic factors to accelerate tumor metastasis. This study was conducted with the objective of investigating the effect of microRNA-23a-3p (miR-23a) on the biological characteristics of OC stem cells by targeting discs large h...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2019.1579960
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Somatostatin receptor scintigraphy (SRS) has been reported for receptor (SSTR) screening in advanced hepatocarcinoma (aHC) prior to somatostatin analogue treatment. AIMS:To evaluate SSTR screening with SRS in aHC patients. RESULTS:Seventy aHC patients (63 men) aged 65 +/- 11 y were included, with alcohol, ...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,多中心研究
doi:10.4161/cbt.8.21.9737
更新日期:2009-11-01 00:00:00