Abstract:
:Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Shelake S,Sankpal UT,Paul Bowman W,Wise M,Ray A,Basha Rdoi
10.1007/s10637-016-0417-9subject
Has Abstractpub_date
2017-04-01 00:00:00pages
158-165issue
2eissn
0167-6997issn
1573-0646pii
10.1007/s10637-016-0417-9journal_volume
35pub_type
杂志文章abstract::Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic dat...
journal_title:Investigational new drugs
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更新日期:2019-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-005-2908-y
更新日期:2005-10-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1026299118067
更新日期:2003-11-01 00:00:00
abstract:PURPOSE:Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested uti...
journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9447-x
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journal_title:Investigational new drugs
pub_type: 杂志文章
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更新日期:1984-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9514-3
更新日期:2011-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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更新日期:1995-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9781-7
更新日期:2012-12-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0206-x
更新日期:2015-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1016261918256
更新日期:2002-08-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1005989519350
更新日期:1997-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
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更新日期:2011-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00173763
更新日期:1989-11-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195368
更新日期:1988-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/b:drug.0000006170.38419.c9
更新日期:2004-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-014-0199-x
更新日期:2015-04-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-014-0132-3
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-006-6886-5
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00171991
更新日期:1990-01-01 00:00:00
abstract::Radioactive iodine-refractory [(18)F] fluorodeoxy-glucose-positron emission tomography-positive thyroid carcinomas represent especially aggressive tumors. Targeting glucose metabolism by the transketolase isoenzyme transketolase like 1 (TKTL-1) which is over-expressed in various neoplasms, may be effective. The correl...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9174-8
更新日期:2009-08-01 00:00:00
abstract::Tyrosine kinase inhibitors (TKI) or monoclonal antibodies targeting EGFR, HER2 or VEGFR receptors have demonstrated substantial clinical benefit in patients with advanced breast cancer, colon cancer, head and neck cancer, non-small cell lung cancer, and renal cell carcinoma. Nevertheless, these drugs have some target ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9252-6
更新日期:2010-06-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/BF00173788
更新日期:1984-01-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0410-3
更新日期:2017-04-01 00:00:00
abstract::Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcriptio...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9917-4
更新日期:2013-08-01 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01052-8
更新日期:2021-01-07 00:00:00
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journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9237-5
更新日期:2010-06-01 00:00:00
abstract::Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted ...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/s10637-011-9758-6
更新日期:2012-10-01 00:00:00
abstract::We previously found that the novel histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) had greater selectivity against cutaneous T-cell lymphoma (CTCL) than SAHA. AN-7 synergizes with doxorubicin (Dox), an anthracycline antibiotic that induces DNA breaks. This study aimed to elucidate the m...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0500-x
更新日期:2018-02-01 00:00:00