Abstract：
:Combining microtubule-targeting antimitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study, we investigate the cellular mechanism by which navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of kinesin-5 (K5I, also called a KSP inhibitor), across a panel of epithelial cancer lines. By using time-lapse microscopy, we showed that navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins, we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest because of an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determines variation in response to antimitotics alone, and antimitotics combined with navitoclax, across our panel. We concluded that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of antimitotic drugs in epithelial cancers, and combination treatment with navitoclax and a spindle specific antimitotic, such as a K5I, might be more effective than paclitaxel alone.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Shi J,Zhou Y,Huang HC,Mitchison TJdoi
10.1158/0008-5472.CAN-10-4336subject
Has Abstractpub_date
2011-07-01 00:00:00pages
4518-26issue
13eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-4336journal_volume
71pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:The presence of a non-small cell lung carcinoma (NSCLC)-related gene or genes on chromosome band 11p15.5 is of particular interest, given the specific loss of heterozygosity (LOH) measured in this region for lung as well as many other pediatric and adult neoplasms. We have undertaken high-density polymorphic marker an...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1996-07-01 00:00:00
abstract：:Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decrease...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-17-1236
更新日期：2018-02-15 00:00:00
abstract：:Recent work on a variety of normal and malignant cell lines has shown that induction and secretion of biologically active TGF-beta may occur after exposure to all-trans-retinoic acid (RA), coincident with decreased growth rate and/or differentiation. This study evaluates the expression and regulation of transforming g...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
abstract：:Retinoic acid (RA) is a potent in vitro inhibitor of cell proliferation in various malignant cell lines. The exact mechanisms of its actions, however, are not fully understood. To further elucidate the nature of this inhibition, we investigated the effects of RA in an estrogen receptor-negative human breast cancer cel...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1996-04-01 00:00:00
abstract：:Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. Dicer is phosphorylated by the ERK-MAP kinase pathway and because this pathway is activ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-2460
更新日期：2019-05-15 00:00:00
abstract：:A crucial ingredient of any hyperthermia procedure is the accurate measurement of achieved temperature. In this paper, we present some accuracy and resolution suggestions and address the problem of temperature measurements when electromagnetic energy is used as the mode of heating. In such cases, conventional metallic...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1979-06-01 00:00:00
abstract：:Angiostatin, a proteolytic fragment of plasminogen, is a potent angiogenesis inhibitor able to suppress tumor growth and metastasis through inhibition of endothelial cell proliferation and migration. Previously, we showed that angiostatin binds and inhibits F(1)F(o) ATP synthase on the endothelial cell surface and tha...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-2806
更新日期：2006-01-15 00:00:00
abstract：:The Salmonella-microsome assay for mutagenesis was used to determine the effect of ozone on the mutagenesis of selected carcinogens and mutagens in water. Short periods of ozonation were shown to completely inactivate the mutagenicity of several polyaromatic amine mutagens including acriflavine, proflavine, and beta-n...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1979-06-01 00:00:00
abstract：:Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumor...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-13-0036
更新日期：2013-09-01 00:00:00
abstract：:ALDH1(+)CD44(+) cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1(+)CD44(+)-HNC...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-12-3840
更新日期：2013-06-01 00:00:00
abstract：:Thyroid tissues in coho salmon (Oncorhynchus kisutch) goiters showed marked regional variation in structure and ultrastructure. For the most part the follicles were small, were composed of tall epithelial cells, and contained little or no colloid material. The follicle epithelial cells were essentially similar in fine...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1978-01-01 00:00:00
abstract：:Several responses of 10T 1/2 cells and of cells from strains transformed by X-irradiation or by methylcholanthrene exposure were examined. Malignant potential, as determined by the ability of the cells to initiate tumors in syngeneic hosts, either normal or rendered immunodeficient, varied by a factor of 10(6). The gr...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1980-10-01 00:00:00
abstract：:The possible involvement of chemical mediator(s) in the induction of the antitumor effects of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on Meth A fibrosarcoma (Meth A) in mice was studied. On day 7 after intradermal implantation of Meth A in mice, rTNF-alpha caused tumor necrosis and inhibited the tum...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1988-08-01 00:00:00
abstract：:The oxidation of the bladder carcinogen 2-naphthylamine (2-NA) by prostaglandin H synthase (PHS) in vitro was examined. Oxygen uptake studies of 2-NA oxidation in the presence of glutathione, as well as extensive product analysis data, are consistent with a one-electron mechanism of 2-NA oxidation by PHS. The formatio...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1987-08-01 00:00:00
abstract：:Fluorescent-labeled hormones can be used to study hormone-receptor interactions by means of fluorescence polarization, visualization by fluorescence microscopy, or separation methods, e.g., dextran-coated charcoal. Subcellular fragments, single cells, and tissue preparations are amenable to study; in this work rat ute...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1978-11-01 00:00:00
abstract：:The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-5575
更新日期：2009-03-15 00:00:00
abstract：:The metabolic changes in rat hepatoma cell line, AH70 cells, after coculturing with Kupffer cells were visualized using a silicon-intensified target camera and subsequent processing with a computer-assisted digital imaging processor. In cocultured tumor cells, nonactivated Kupffer cells reduced mitochondrial energizat...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1993-06-01 00:00:00
abstract：:Expression of transforming growth factor beta 1 (TGF beta 1) protein was examined in chemically induced benign skin tumors with genetically defined empirical risks for malignant conversion. Benign tumors induced in mice which have both alleles of the p53 gene deleted have a malignant conversion frequency of approximat...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1994-11-15 00:00:00
abstract：:A series of linkage studies was previously conducted to identify quantitative trait loci associated with chemically induced lung tumors. However, little is known of genetic susceptibility to spontaneously occurring lung tumorigenesis (SLT) in mice. In this study, we did a whole-genome linkage disequilibrium analysis f...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-1508
更新日期：2005-09-15 00:00:00
abstract：:Proteolysis-inducing factor (PIF) is a sulfated glycoprotein produced by cachexia-inducing tumors, which induces atrophy of skeletal muscle. PIF has been shown to bind specifically with high affinity (K(d), in nanomolar) to sarcolemma membranes from skeletal muscle of both the mouse and the pig, as well as murine myob...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-2602
更新日期：2007-12-01 00:00:00
abstract：:The cell surface molecules controlling apoptosis in cortical neurons are largely unknown. A monoclonal antibody was derived that induces cultured neocortical neurons to undergo apoptosis. A Fab fragment of the antibody, however, lacked the ability to induce cell death. The antigen was purified, and characterized by co...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-08-01 00:00:00
abstract：:Although regulatory T cells (Tregs) have been detected in clinically apparent and experimentally induced tumors, the significance of their presence is obscured because past studies examined late-stage tumors that had formed in immunocompetent hosts and thus had evolved mechanisms to escape immunologic recognition and/...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-0556
更新日期：2006-07-15 00:00:00
abstract：:Fibroblast growth factor (FGF) 8, also known as androgen-induced growth factor, was originally isolated from an androgen-dependent mouse mammary Shionogi carcinoma SC-3 cell line, in which it was shown to have androgen-regulated properties. We previously demonstrated that Fgf 8 transcripts were detected in several hum...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1998-05-15 00:00:00
abstract：:The effect of dietary orotic acid (OA) in liver-pancreas carcinogenesis induced in female Syrian hamsters by N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) was evaluated. All animals infused with the carcinogen received the same doses. Results of the control group which received no OA or carcinogen were compared...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1994-10-15 00:00:00
abstract：:IL6-PE40 and IL6-PE664Glu are chimeric molecules composed of interleukin 6 (IL6) fused to a truncated form (PE40) or a full-length mutated form (PE664Glu) of Pseudomonas exotoxin. Both forms of IL6-Pseudomonas exotoxin are cytotoxic to IL6 receptor-bearing tumor cell types in culture. In this report, we show that both...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-06-01 00:00:00
abstract：:Previous studies have shown that enforced expression of IFN-beta suppressed tumor growth and metastasis. In this report, we determined whether the induction of nitric oxide synthase II (NOS II) gene is required for IFN-beta-mediated antitumor activity using syngeneic mice with intact (NOS II+/+) or genetically disrupt...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-01-01 00:00:00
abstract：:Administration of methylating carcinogens such as methyl methanesulfonate (120 mg/kg), dimethylnitrosamine (5 mg/kg), or methylnitrosourea (80 mg/kg) to rats resulted in an increased ellipticity in circular dichroism spectra and in an enhanced ability to bind ethidium bromide in the liver chromatin. Although shearing ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1976-05-01 00:00:00
abstract：:The effects of the anthracycline antiboties, daunomycin and adriamycin, on the DNA-directed activities of DNA polymerases from murine sarcoma virus, rat liver (high-molecular-weight species), Escherichia coli, and Micrococcus luteus were determined. Under all conditions tested, these compounds had greater inhibitory e...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1975-03-01 00:00:00
abstract：:DNA topoisomerase I (topo I) has been identified as a principal target of a plant alkaloid camptothecin (CPT) and its derivative (CPT-11). The latter compound is expected to be a clinically useful antitumor agent. Three human tumor cell lines resistant to CPT (A549/CPT, HT-29/CPT, St-4/CPT) were isolated in vitro, and...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-11-01 00:00:00
abstract：:Immunotoxins directed against human transferrin receptor have been evaluated in a nude mouse model of human malignant mesothelioma. Immunotoxins were constructed by linking ricin A chain to murine monoclonal antibodies reactive with the human transferrin receptor. A chain was obtained either by isolation from the pare...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1987-08-15 00:00:00
