MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death.

Abstract:

:Novel therapeutic approaches are urgently needed for high-stage neuroblastoma, a major therapeutic challenge in pediatric oncology. The majority of neuroblastoma tumors are p53 wild type with intact downstream p53 signaling pathways. We hypothesize that stabilization of p53 would sensitize this aggressive tumor to genotoxic chemotherapy via inhibition of MDM2, the primary negative upstream regulator of p53. We used pharmacologic inhibition of the MDM2-p53 interaction with the small-molecule inhibitor Nutlin and studied the subsequent response to chemotherapy in neuroblastoma cell lines. We did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase assays to measure proliferation and apoptosis in several cell lines (IMR32, MYCN3, and JF) treated with combinations of cisplatin, etoposide, and Nutlin. We found consistent and robust decreases in proliferation and increases in apoptosis with the addition of Nutlin 3a to etoposide or cisplatin in all cell lines tested and no response to the inactive Nutlin 3b enantiomer. We also show a rapid and robust accumulation of p53 protein by Western blot in these cells within 1 to 2 hours of treatment. We conclude that MDM2 inhibition dramatically enhances the activity of genotoxic drugs in neuroblastoma and should be considered as an adjuvant to chemotherapy for this aggressive pediatric cancer and for possibly other p53 wild-type solid tumors.

journal_name

Mol Cancer Ther

authors

Barbieri E,Mehta P,Chen Z,Zhang L,Slack A,Berg S,Shohet JM

doi

10.1158/1535-7163.MCT-06-0305

subject

Has Abstract

pub_date

2006-09-01 00:00:00

pages

2358-65

issue

9

eissn

1535-7163

issn

1538-8514

pii

5/9/2358

journal_volume

5

pub_type

杂志文章
  • Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies.

    abstract::TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-20-0464

    authors: Preillon J,Cuende J,Rabolli V,Garnero L,Mercier M,Wald N,Pappalardo A,Denies S,Jamart D,Michaux AC,Pirson R,Pitard V,Bagot M,Prasad S,Houthuys E,Brouwer M,Marillier R,Lambolez F,Marchante JR,Nyawouame F,Carter MJ

    更新日期:2021-01-01 00:00:00

  • Dual targeting of tumor angiogenesis and chemotherapy by endostatin-cytosine deaminase-uracil phosphoribosyltransferase.

    abstract::Several antiangiogenic drugs targeting VEGF/VEGF receptor (VEGFR) that were approved by the Food and Drug Administration for many cancer types, including colorectal and lung cancer, can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will probably influence the normal function of endothe...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-1117

    authors: Chen CT,Yamaguchi H,Lee HJ,Du Y,Lee HH,Xia W,Yu WH,Hsu JL,Yen CJ,Sun HL,Wang Y,Yeh ET,Hortobagyi GN,Hung MC

    更新日期:2011-08-01 00:00:00

  • Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-κB.

    abstract::Zoledronic acid, a third-generation bisphosphonate, has been shown to reduce cell migration, invasion, and metastasis. However, the effects of zoledronic acid on the epithelial-mesenchymal transition (EMT), a cellular process essential to the metastatic cascade, remain unclear. Therefore, the effects of zoledronic aci...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0304

    authors: Schech AJ,Kazi AA,Gilani RA,Brodie AH

    更新日期:2013-07-01 00:00:00

  • Algorithmic guided screening of drug combinations of arbitrary size for activity against cancer cells.

    abstract::The standard treatment for most advanced cancers is multidrug therapy. Unfortunately, combinations in the clinic often do not perform as predicted. Therefore, to complement identifying rational drug combinations based on biological assumptions, we hypothesized that a functional screen of drug combinations, without lim...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0937

    authors: Zinner RG,Barrett BL,Popova E,Damien P,Volgin AY,Gelovani JG,Lotan R,Tran HT,Pisano C,Mills GB,Mao L,Hong WK,Lippman SM,Miller JH

    更新日期:2009-03-01 00:00:00

  • Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.

    abstract::There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue c...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0926

    authors: Musa F,Alard A,David-West G,Curtin JP,Blank SV,Schneider RJ

    更新日期:2016-07-01 00:00:00

  • Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2.

    abstract::The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to dr...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0669

    authors: Soares HP,Ming M,Mellon M,Young SH,Han L,Sinnet-Smith J,Rozengurt E

    更新日期:2015-04-01 00:00:00

  • Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer.

    abstract::Several studies have shown antitumor activities of the melanoma differentiation-associated gene 7 (mda-7) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previously been tested. There...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Oida Y,Gopalan B,Miyahara R,Inoue S,Branch CD,Mhashilkar AM,Lin E,Bekele BN,Roth JA,Chada S,Ramesh R

    更新日期:2005-02-01 00:00:00

  • Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts.

    abstract::Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0280

    authors: Roland CL,Dineen SP,Lynn KD,Sullivan LA,Dellinger MT,Sadegh L,Sullivan JP,Shames DS,Brekken RA

    更新日期:2009-07-01 00:00:00

  • Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.

    abstract::B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0449

    authors: Mitsiades CS,Negri J,McMullan C,McMillin DW,Sozopoulos E,Fanourakis G,Voutsinas G,Tseleni-Balafouta S,Poulaki V,Batt D,Mitsiades N

    更新日期:2007-03-01 00:00:00

  • Targeting of BRM Sensitizes BRG1-Mutant Lung Cancer Cell Lines to Radiotherapy.

    abstract::Targeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here, we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically non-small...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0067

    authors: Zernickel E,Sak A,Riaz A,Klein D,Groneberg M,Stuschke M

    更新日期:2019-03-01 00:00:00

  • Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

    abstract::Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity cou...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0985

    authors: Amodio N,Stamato MA,Gullà AM,Morelli E,Romeo E,Raimondi L,Pitari MR,Ferrandino I,Misso G,Caraglia M,Perrotta I,Neri A,Fulciniti M,Rolfo C,Anderson KC,Munshi NC,Tagliaferri P,Tassone P

    更新日期:2016-06-01 00:00:00

  • A novel two-step transcriptional activation system for gene therapy directed toward epithelial cells.

    abstract::The two-step transcriptional activation (TSTA) mechanism in gene therapy amplifies cell type-specific promoter activity, allowing for increased levels of gene expression in target tissues. In this system, the specific promoter drives expression of a strong transcriptional activator that binds to DNA target sequences l...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0543

    authors: Arendt ML,Nasir L,Morgan IM

    更新日期:2009-12-01 00:00:00

  • (-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance.

    abstract::Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X(L), contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, wa...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Oliver CL,Miranda MB,Shangary S,Land S,Wang S,Johnson DE

    更新日期:2005-01-01 00:00:00

  • Quinacrine overcomes resistance to erlotinib by inhibiting FACT, NF-κB, and cell-cycle progression in non-small cell lung cancer.

    abstract::Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest because many tumors express wild-type (wt) EGFR or develop a second-site EGFR mutation. To test drug combinatio...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0013

    authors: Dermawan JK,Gurova K,Pink J,Dowlati A,De S,Narla G,Sharma N,Stark GR

    更新日期:2014-09-01 00:00:00

  • Shedding Light on the Dark Cancer Genomes: Long Noncoding RNAs as Novel Biomarkers and Potential Therapeutic Targets for Cancer.

    abstract::Recently there have been explosive discoveries of new long noncoding RNAs (lncRNA) obtained by progress in the technology of second-generation sequencing. Genome scale analysis of transcriptome, in conjunction with studies on chromatin modifications at the epigenetic level, identified lncRNAs as a novel type of noncod...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-18-0124

    authors: Zhang L,Peng D,Sood AK,Dang CV,Zhong X

    更新日期:2018-09-01 00:00:00

  • Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.

    abstract::Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0006-T

    authors: Cheng KW,Wong CC,Alston N,Mackenzie GG,Huang L,Ouyang N,Xie G,Wiedmann T,Rigas B

    更新日期:2013-08-01 00:00:00

  • The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia.

    abstract::Proteasome inhibitors are potent inducers of apoptosis in isolated lymphocytes from patients with chronic lymphocytic leukemia (CLL). However, the reversible proteasome inhibitor bortezomib (PS-341; Velcade) did not display substantial antitumor activity in CLL patients. Here, we compared the effects of bortezomib and...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0066

    authors: Ruiz S,Krupnik Y,Keating M,Chandra J,Palladino M,McConkey D

    更新日期:2006-07-01 00:00:00

  • Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.

    abstract::There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0098

    authors: Williams TM,Flecha AR,Keller P,Ram A,Karnak D,Galbán S,Galbán CJ,Ross BD,Lawrence TS,Rehemtulla A,Sebolt-Leopold J

    更新日期:2012-05-01 00:00:00

  • The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells.

    abstract::The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Wu T,Leng J,Han C,Demetris AJ

    更新日期:2004-03-01 00:00:00

  • Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid-Derived Suppressor Cells.

    abstract::Myeloid-derived suppressor cells (MDSC) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T-cell-mediated antitumor immunity, but mechanisms remain ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0981

    authors: Plebanek MP,Bhaumik D,Bryce PJ,Thaxton CS

    更新日期:2018-03-01 00:00:00

  • Discovery and development of anticancer aptamers.

    abstract::Aptamers, also termed as decoys or "chemical antibodies," represent an emerging class of therapeutics. They are short DNA or RNA oligonucleotides or peptides that assume a specific and stable three-dimensional shape in vivo, thereby providing specific tight binding to protein targets. In some cases and as opposed to a...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-06-0172

    authors: Ireson CR,Kelland LR

    更新日期:2006-12-01 00:00:00

  • Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells.

    abstract::Chemoresistance of ovarian carcinoma has been associated previously to the absence of Bcl-x(L) expression downregulation in response to cisplatin. Among BH3-mimetic molecules constituting promising anticancer agents able to inhibit the activity of antiapoptotic Bcl-2 family proteins, we evaluated the effect of one of ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0493

    authors: Simonin K,Brotin E,Dufort S,Dutoit S,Goux D,N'diaye M,Denoyelle C,Gauduchon P,Poulain L

    更新日期:2009-11-01 00:00:00

  • Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth.

    abstract::Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., (V600E)B-Raf A375, IC(50) on cells = 2 nmol/L; ED(50) on...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0181

    authors: Carnahan J,Beltran PJ,Babij C,Le Q,Rose MJ,Vonderfecht S,Kim JL,Smith AL,Nagapudi K,Broome MA,Fernando M,Kha H,Belmontes B,Radinsky R,Kendall R,Burgess TL

    更新日期:2010-08-01 00:00:00

  • C35 (C17orf37) is a novel tumor biomarker abundantly expressed in breast cancer.

    abstract::Identification of shared tumor-specific targets is useful in developing broadly applicable therapies. In a study designed to identify genes up-regulated in breast cancer, a cDNA clone corresponding to a novel gene C35 (C17orf37) was selected by representational difference analysis of tumor and normal human mammary cel...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0389

    authors: Evans EE,Henn AD,Jonason A,Paris MJ,Schiffhauer LM,Borrello MA,Smith ES,Sahasrabudhe DM,Zauderer M

    更新日期:2006-11-01 00:00:00

  • Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells.

    abstract::Antioxidants, such as vitamin E, are being investigated for efficacy in prostate cancer prevention. In this study, we show that the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), has antiandrogen activity in prostate carcinoma cells. In the presence of PMCol, the androgen-stimulated biphas...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Thompson TA,Wilding G

    更新日期:2003-08-01 00:00:00

  • Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor.

    abstract::Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-1009

    authors: Takezawa K,Okamoto I,Tanizaki J,Kuwata K,Yamaguchi H,Fukuoka M,Nishio K,Nakagawa K

    更新日期:2010-06-01 00:00:00

  • Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.

    abstract::Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do i...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0012

    authors: Iida M,Bahrar H,Brand TM,Pearson HE,Coan JP,Orbuch RA,Flanigan BG,Swick AD,Prabakaran PJ,Lantto J,Horak ID,Kragh M,Salgia R,Kimple RJ,Wheeler DL

    更新日期:2016-09-01 00:00:00

  • Synergistic enhancement of TRAIL- and tumor necrosis factor alpha-induced cell death by a phenoxazine derivative.

    abstract::2-Amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1) has been developed as a novel phenoxazine derivative having an anticancer activity on a variety of cancer cell lines as well as transplanted tumors in mice with minimal toxicity to normal cells. We examined the effects of Phx-1 on Jurkat cells, a ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0067

    authors: Hara K,Okamoto M,Aki T,Yagita H,Tanaka H,Mizukami Y,Nakamura H,Tomoda A,Hamasaki N,Kang D

    更新日期:2005-07-01 00:00:00

  • The synthetic caged garcinia xanthone cluvenone induces cell stress and apoptosis and has immune modulatory activity.

    abstract::Several caged Garcinia xanthone natural products have potent bioactivity and a documented value in traditional Eastern medicine. Previous synthesis and structure activity relationship studies of these natural products resulted in the identification of the pharmacophore represented by the structure of cluvenone. In the...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0517

    authors: Batova A,Altomare D,Chantarasriwong O,Ohlsen KL,Creek KE,Lin YC,Messersmith A,Yu AL,Yu J,Theodorakis EA

    更新日期:2010-11-01 00:00:00

  • Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer.

    abstract::The majority of patients with HER2-overexpressing metastatic breast cancer who initially respond to the HER2-targeted antibody trastuzumab show disease progression within 1 year. The identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical for imp...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0012

    authors: Rowe DL,Ozbay T,Bender LM,Nahta R

    更新日期:2008-07-01 00:00:00