Abstract:
BACKGROUND:Chemotherapy and targeted therapies have made important strides in cancer treatment yet they often fail and new therapies are still needed. Here, we employed a phenotypic screen to identify and analyze the mechanism of action of novel small molecules that interfere with critical pathways involved in tumor cell growth, using chemoresistant A375 melanoma cells as a model. METHODS:Cell culture studies were performed in ATCC-recommended media. Compounds, and compound libraries were obtained from Boston University or purchased commercially. Effects on A375 cell viability, proliferation and morphology were determined by Celigo Image Cytometer and viability staining. Anticancer activity of the lead compound was tested in a xenograft nude mouse model. Signaling and cell death pathways were analyzed by SDS-PAGE and immunoblotting, and/or fluorescence microscopy. RESULTS:After evaluating 4477 compounds, one hit compound CB533 was identified that caused significant reduction of A375 cell growth. CB533 is an unexplored 1,4-naphthoquinone (NQ) derivative which unlike 1,4-NQ, induced rapid cell death without generating reactive oxygen species (ROS). Structure-activity relationship analysis showed that a pyrrolidine in the 1,4-NQ nucleus in lead compound Pyr-1 yielded optimal activity. CB533 and Pyr-1 had growth-suppressing effects on a large variety of chemotherapy-resistant cancer cell lines in the nano to picomolar range. Pyr-1 also significantly reduced growth of MDA-MB-231 breast cancer cells in nude mice. Pyr-1 rapidly induced activation of major stress pathways and autophagy, which was efficiently blocked by ERK, and somewhat by PI3K inhibitors. CONCLUSION:CB533 and lead Pyr-1 represent novel broad-spectrum, anticancer compounds that are up to 1000-fold more potent than plumbagin, a natural 1,4-NQ with known anticancer activity. Since the growth suppression activities of CB533 and Pyr-1 are unaffected by the chemotherapy resistance of cancer cells, these compounds have promising therapeutic potential. The pyrrolidine in the 3 position of the 1,4-NQ nucleus of Pyr-1 is a critical component of the pharmacophore. Pyr-1-induced cellular stress was mediated by an ERK, and to a lesser extent by an AKT-dependent pathway without involving apoptosis. Our data suggest that Pyr-1 derives its greatly enhanced antitumor activity via mimicking ROS-induced stress signaling without generating ROS, and likely committing cells to autophagy.
journal_name
J Biomed Scijournal_title
Journal of biomedical scienceauthors
Ghosh SK,Ganta A,Spanjaard RAdoi
10.1186/s12929-018-0408-6subject
Has Abstractpub_date
2018-02-08 00:00:00pages
12issue
1eissn
1021-7770issn
1423-0127pii
10.1186/s12929-018-0408-6journal_volume
25pub_type
杂志文章abstract::Plasma nitric oxide (NO) levels in Duchenne muscular dystrophy (DMD) patients were significantly lower than those observed in both healthy controls and in patients with other neuromuscular disorders. The correlation between NO level and ejection fraction was significant (r = -0.384, p = 0.0391) in the DMD group. Disru...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02256104
更新日期:2004-07-01 00:00:00
abstract::A three-dimensional molecular model of the transmembrane domain of the 5-HT(1A) receptor (5-HT(1A)R) is presented in the context of a general strategy for modeling the macromolecular structure of a guanine nucleotide binding, regulatory protein coupled receptor (GPCR). The model of the 5-HT(1A)R rests on the definitio...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255537
更新日期:1996-04-01 00:00:00
abstract::An isolated thoracic spinal cord of the neonatal rat in vitro spontaneously generates sympathetic nerve discharge (SND) at ~25 degrees C, but it fails in SND genesis at < or = 10 degrees C. Basal levels of the c-Fos expression in the spinal cords incubated at < or = 10 degrees C and ~25 degrees C were compared to dete...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/1423-0127-16-44
更新日期:2009-05-01 00:00:00
abstract:BACKGROUND:Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-014-0074-2
更新日期:2014-08-06 00:00:00
abstract::Glucocorticoids regulate the expression of many liver-specific genes via glucocorticoid receptors. The presence of glucocorticoid receptors in liver has been reported in many mammalian species but not in nude mice. In the present study, we demonstrate the presence of specific glucocorticoid receptors in nude mouse liv...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02253306
更新日期:1994-10-01 00:00:00
abstract::Purinergic P2X7 receptor (P2X7R), an ATP-gated cation channel, is unique among all other family members because of its ability to respond to various stimuli and to modulate pro-inflammatory signaling. The activation of P2X7R in immune cells is absolutely required for mature interleukin -1beta (IL-1beta) and IL-18 prod...
journal_title:Journal of biomedical science
pub_type: 杂志文章,评审
doi:10.1186/1423-0127-20-26
更新日期:2013-05-01 00:00:00
abstract::The present study was undertaken to elucidate the mechanism of intra-arterial propofol-induced vascular permeability change resulting in tissue edema. The mechanism of propofol-induced hyperpermeability was examined in a rat femoral artery injection model. Vascular permeability was determined by measuring the Evans bl...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/s11373-007-9164-4
更新日期:2007-09-01 00:00:00
abstract::The SARS related Coronavirus genome contains a variety of novel accessory genes. One of these, called ORF7a or ORF8, code for a protein, known as 7a, U122 or X4. We set out to determine the three-dimensional structure of the soluble ectodomain of this type-I transmembrane protein by nuclear magnetic resonance spectros...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/s11373-005-9043-9
更新日期:2006-05-01 00:00:00
abstract::The Tat proteins of human immunodeficiency virus types 1 (HIV-1) and 2 (HIV-2), termed Tat-1 and Tat-2, respectively, are essential for efficient viral replication. Tat proteins activate viral transcription by binding to the TAR RNA stem-loop structure at the 5' end of viral transcripts. We used an in vitro selection ...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255590
更新日期:1997-01-01 00:00:00
abstract::The intracellular mechanisms underlying oxidized low-density lipoprotein (oxLDL)-signaling pathways in platelets are not yet completely understood. Therefore, the aim of this study was to further examine the effects of oxLDL in prevention of platelet aggregation. In this study, oxLDL concentration-dependently (40-120 ...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/s11373-005-9042-x
更新日期:2006-05-01 00:00:00
abstract:BACKGROUND:Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock. METHODS:Anesthetized male ...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-017-0316-1
更新日期:2017-01-17 00:00:00
abstract:BACKGROUND:Detection of cholangiocarcinoma (CCA) remains a diagnostic challenge. We established diagnostic peptide biomarkers in bile and urine based on capillary electrophoresis coupled to mass spectrometry (CE-MS) to detect both local and systemic changes during CCA progression. In a prospective cohort study we recen...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-019-0599-5
更新日期:2020-01-03 00:00:00
abstract::Experimental allergic encephalomyelitis (EAE) is an accepted animal model for the human demyelinating disease multiple sclerosis. The continuously propagated line of Lewis rat T helper lymphocytes (GP1 T cells), specific for the encephalitogenic 68-86 sequence of guinea pig myelin basic protein (GPMBP), mediates the a...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255600
更新日期:1997-03-01 00:00:00
abstract::Based on the tertiary structure of the ribosome-inactivating protein alpha-sarcin, domains that are responsible for hydrolyzing ribosomes and naked RNA have been dissected. In this study, we found that the head-to-tail interaction between the first amino beta-strand and the last carboxyl beta-strand is not involved in...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255817
更新日期:2000-09-01 00:00:00
abstract::The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesth...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02253100
更新日期:1996-05-01 00:00:00
abstract::The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of mu-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated mu-opioid peptide endomorphins can activate G proteins through mu-opioid receptors in the PAG by monitoring th...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255469
更新日期:2000-05-01 00:00:00
abstract::After streptococcal pyrogenic exotoxin B (SPE B) induces apoptosis, its fate is unknown. Using confocal time-course microscopy at 37 degrees C, we detected green fluorescence 20 min after adding FITC-SPE B. Orange fluorescence, an indication of co-localization of SPE B with lysosomes which were labeled with a red fluo...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/s11373-007-9154-6
更新日期:2007-05-01 00:00:00
abstract::The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) promoter 1 (LP1) is an inducible and cell type-specific promoter involved in regulating the production of an 8.3-kb primary LAT transcript during acute and latent infection of peripheral sensory neurons and during subsequent virus reactivation...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02255935
更新日期:1998-11-01 00:00:00
abstract::We studied 42 individuals, including 8 patients with either complete or partial syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), 8 patients with either complete or partial syndrome of myoclonic epilepsy with ragged-red fibers (MERRF) and 26 maternal family members w...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1159/000064725
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND:Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutat...
journal_title:Journal of biomedical science
pub_type: 杂志文章,评审
doi:10.1186/s12929-018-0442-4
更新日期:2018-06-02 00:00:00
abstract:BACKGROUND:Poly(ADP-ribose) is a NAD+-requiring, DNA-repairing, enzyme playing a central role in pancreatic beta-cell death and in the development of endothelial dysfunction in humans and experimental animals. PARP activation is also relevant to the development of complications of diabetes. Hence, agents capable of inh...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/1423-0127-17-S1-S16
更新日期:2010-08-24 00:00:00
abstract::Death-associated protein (DAP)-kinase, an actin-cytoskeleton localized serine/threonine kinase, functions as a novel tumor suppressor and participates in a wide variety of cell death systems. Recent studies indicate that DAP-kinase elicits a potent cytoskeletal reorganization effect and is capable of modulating integr...
journal_title:Journal of biomedical science
pub_type: 杂志文章,评审
doi:10.1007/s11373-005-9063-5
更新日期:2006-03-01 00:00:00
abstract:BACKGROUND:Despite the recent progress in screening and therapy, a majority of prostate cancer cases eventually attain hormone refractory and chemo-resistant attributes. Conventional chemotherapeutic strategies are effective at very high doses for only palliative management of these prostate cancers. Therefore chemo-se...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-015-0127-1
更新日期:2015-04-01 00:00:00
abstract::Drosophila eye development is a progressive process including cell fate determination, pattern formation, and rhabdomere morphogenesis. During eye development, a dramatic change in cell shape, which involves turning and extension of the photoreceptor apical surface, occurs in the early pupal stages. It is known that a...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/BF02254441
更新日期:2004-05-01 00:00:00
abstract:BACKGROUND:NKG2D, an activating immunoreceptor, is primarily restricted to NK cells and CD8(+) T cells. The existence of an atypical cytotoxic CD4(+)NKG2D(+) T cell population has also been found in patients with autoimmune dysfunctions. Nonetheless, contradictory evidence has categorized this population with a regulat...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-015-0190-7
更新日期:2015-10-20 00:00:00
abstract:INTRODUCTION:Head and neck squamous carcinoma (HNSCC) is one of the most invasive types of cancer with high mortality. A previous study has indicated that low levels of let-7d and miR-205 in HNSCC patients are correlated with poor survival. Let-7d and miR-205 are tumor suppressors and regulators of epithelial-to-mesenc...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-019-0511-3
更新日期:2019-02-13 00:00:00
abstract:BACKGROUND:This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/s12929-015-0198-z
更新日期:2015-12-08 00:00:00
abstract:BACKGROUND:Previous study demonstrated the improvement of cardiac function was proportional to the number of cells implanted. Therefore, increasing cell survival in the infarcted myocardium might contribute to the improvement of the functional benefit of cell transplantation. METHODS AND RESULTS:MSCs were treated with...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1007/s11373-007-9207-x
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND:Zerumbone, a sesquiterpene compound isolated from subtropical ginger, Zingiber zerumbet Smith, has been documented to exert antitumoral and anti- inflammatory activities. In this study, we demonstrate that zerumbone induces apoptosis in human glioblastoma multiforme (GBM8401) cells and investigate the apopto...
journal_title:Journal of biomedical science
pub_type: 杂志文章
doi:10.1186/1423-0127-19-86
更新日期:2012-10-05 00:00:00
abstract::In many solid tumor types, tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME). Moreover, TAMs infiltration is strongly associated with poor survival in solid tumor patients. In this review, we describe the origins of TAMs and their polarization state dictated by the TME. W...
journal_title:Journal of biomedical science
pub_type: 杂志文章,评审
doi:10.1186/s12929-019-0568-z
更新日期:2019-10-20 00:00:00