Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease.

Abstract:

:Several studies have established a link between aberrant PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling and neuroendocrine tumor disease. In this study, we comparatively investigate the antitumor potential of novel small-molecule inhibitors targeting mTOR (RAD001), mTOR/PI(3)K (NVP-BEZ235) and Raf (Raf265) on human NET cell lines of heterogeneous origin. All inhibitors induced potent antitumor effects which involved the induction of apoptosis and G0/G1 arrest. However, the dual mTOR/PI(3)K inhibitor NVP-BEZ235 was more efficient compared to the single mTOR inhibitor RAD001. Consistently, NVP-BEZ235 prevented the negative feedback activation of Akt as observed after treatment with RAD001. Raf265 inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion, suggesting the existence of a compensatory feedback loop on PI3K-Akt signaling. Finally, combined treatment with RAD001 or NVP-BEZ235 and Raf265 was more efficient than single treatment with either kinase inhibitor. Together, our data provide a rationale for dual targeting of PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling in NET disease.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Zitzmann K,Rüden Jv,Brand S,Göke B,Lichtl J,Spöttl G,Auernhammer CJ

doi

10.1016/j.canlet.2010.02.018

subject

Has Abstract

pub_date

2010-09-01 00:00:00

pages

100-9

issue

1

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(10)00119-9

journal_volume

295

pub_type

杂志文章
  • The effects of ellagic acid and 13-cis-retinoic acid on N-nitrosobenzylmethylamine-induced esophageal tumorigenesis in rats.

    abstract::Ellagic acid (EA) and 13-cis-retinoic acid (CRA), both alone and in combination, were tested for their ability to inhibit N-nitrosobenzylmethylamine-induced tumors in the rat esophagus. Groups of male rats were fed AIN-76A diet containing EA (4 g/kg), CRA (240 mg/kg), or a combination of EA and CRA (4 g/kg and 240 mg/...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(91)90085-v

    authors: Daniel EM,Stoner GD

    更新日期:1991-02-01 00:00:00

  • Antibody-induced apoptosis in a human leukemia cell line is energy dependent: thermochemical analysis of cellular metabolism.

    abstract::The mouse monoclonal anti-BAL antibody induced apoptosis in a pre-B acute lymphocytic leukemia cell line within 2 days of incubation, after being crosslinked by a secondary antibody. The antibody specifically recognized a 37 kDa membrane protein that was expressed on a wide spectrum of normal and malignant cells, but ...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(93)90194-e

    authors: Wallén-Ohman M,Lönnbro P,Schön A,Borrebaeck CA

    更新日期:1993-12-10 00:00:00

  • CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people.

    abstract::CYP1A1, CYP2E1 and GSTM1 polymorphisms were evaluated in Chilean healthy controls and lung cancer patients. In the Chilean healthy group, frequencies of CYP1A1 variant alleles for MspI (m2 or CYP1A1*2A) and ile/val (val or CYP1A1*2B) polymorphisms were 0.25 and 0.33, respectively. Frequencies of variant alleles C (CYP...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(01)00686-3

    authors: Quiñones L,Lucas D,Godoy J,Cáceres D,Berthou F,Varela N,Lee K,Acevedo C,Martínez L,Aguilera AM,Gil L

    更新日期:2001-12-10 00:00:00

  • Omics-based nanomedicine: the future of personalized oncology.

    abstract::The traditional "one treatment fits all" paradigm disregards the heterogeneity between cancer patients, and within a particular tumor, thus limit the success of common treatments. Moreover, current treatment lacks specificity and therefore most of the anticancer drugs induce severe adverse effects. Personalized medici...

    journal_title:Cancer letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.canlet.2013.07.029

    authors: Rosenblum D,Peer D

    更新日期:2014-09-28 00:00:00

  • Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer.

    abstract::A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main source of energy. Lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability o...

    journal_title:Cancer letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.canlet.2014.12.035

    authors: Augoff K,Hryniewicz-Jankowska A,Tabola R

    更新日期:2015-03-01 00:00:00

  • Cellular uptake and photosensitizing properties of hematoporphyrin di-ethers with similar chromatographic properties as the tumorlocalizing fraction of hematoporphyrin derivative.

    abstract::The di-methyl-, di-ethyl-, di-propyl-, di-normal butyl-, and di-iso-butyl-ethers of hematoporphyrin were synthesized and shown to possess chromatographic properties similar to those of the tumorlocalizing components of hematoporphyrin derivative (Hpd). The cellular uptake of these ethers, as well as their retention in...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(87)90178-9

    authors: Moan J,Rimington C,Sommer S

    更新日期:1987-03-01 00:00:00

  • Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan.

    abstract::To define the critical region of liver-specific tumor suppressor genes in human hepatocellular carcinoma (HCC), we analyzed 30 cases of hepatocellular carcinoma using nine 4q and six 16q microsatellite polymorphic DNA markers. We observed one major common deleted region which was flanked by D4S175-D4S1625 and there ma...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(97)00276-0

    authors: Chou YH,Chung KC,Jeng LB,Chen TC,Liaw YF

    更新日期:1998-01-16 00:00:00

  • Effect of cis-unsaturated fatty acids on Meth-A ascitic tumour cells in vitro and in vivo.

    abstract::Earlier studies performed both by us and by others have demonstrated that some n-3 and n-6 fatty acids can inhibit the growth of tumour cells in vitro. Though studies done with various types of oils rich in n-3 and n-6 fatty acids did show that the tumour incidence and growth can be modified, there were relatively few...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(97)00426-6

    authors: Ramesh G,Das UN

    更新日期:1998-01-30 00:00:00

  • Fluorescence photography as a diagnostic method for oral cancer.

    abstract::This study was carried out to evaluate the diagnostic utility of autofluorescence photography for oral mucosal lesions. The materials consisted of 15 chemically-induced lesions containing carcinomas in 15 hamsters, and 32 oral lesions in 30 patients. In the animal models, orange fluorescence was detected in all squamo...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(96)04388-1

    authors: Onizawa K,Saginoya H,Furuya Y,Yoshida H

    更新日期:1996-11-12 00:00:00

  • The expression of the myc proto-oncogene in a dimethylsulfoxide resistant HL-60 cell line.

    abstract::A cell line partially resistant to dimethylsulfoxide (DMSO) was derived from the HL-60 cell line. Cycloleucine, theophylline, sodium butyrate and elevated levels of DMSO were found to induce myeloid differentiation in this cell line while TPA induced monocytic differentiation. The levels of myc RNA and the genomic str...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(84)90043-0

    authors: Grosso LE,Pitot HC

    更新日期:1984-02-01 00:00:00

  • Growth suppression and apoptosis induction in synovial sarcoma cell lines by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ).

    abstract::Synovial sarcoma is a relatively common soft tissue sarcoma with an aggressive clinical course. Although surgery is currently the first treatment modality, improvement of adjuvant chemotherapy is deemed essential to improve the clinical outcome. Nuclear factor-kappaB (NF-kappaB) is constitutively activated in various ...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2008.07.021

    authors: Horiuchi K,Morioka H,Nishimoto K,Suzuki Y,Susa M,Nakayama R,Kawai A,Sonobe H,Takaishi H,Ozaki T,Yabe H,Umezawa K,Toyama Y

    更新日期:2008-12-18 00:00:00

  • TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade.

    abstract::Aberrant activation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss or inactivation of TSC1/TSC2 protein complex, leads to negative feedback inhibition of Akt. The exact mechanisms of this process are still not fully understood. Here we present evidence for the involvement of STAT3, a known mTORC1 ...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2011.09.006

    authors: Zha X,Hu Z,He S,Wang F,Shen H,Zhang H

    更新日期:2011-12-27 00:00:00

  • Regulat-INGs in tumors and diseases: Focus on ncRNAs.

    abstract::ING family genes (Inhibitor of Growth) are tumor suppressor genes that play a vital role in cell homeostasis. It has been shown that their expression is lost or diminished in many cancers and other diseases. The main mechanisms by which they are regulated in oncogenesis have not yet been fully elucidated. The involvem...

    journal_title:Cancer letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.canlet.2019.01.006

    authors: Gournay M,Paineau M,Archambeau J,Pedeux R

    更新日期:2019-04-10 00:00:00

  • Drug accumulation and DNA platination in cells exposed to aquated cisplatin species.

    abstract::Since CP always exists in aqueous solution as a mixture of native drug and various aqua and hydroxo species, it is conceivable that one or more of these aquated species is the main form of the drug that enters the cell. To test this hypothesis, we examined the accumulation by 2008 human ovarian carcinoma cells of CP a...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(94)90205-4

    authors: Jennerwein M,Andrews PA

    更新日期:1994-06-30 00:00:00

  • Metabolic tumor burden: a new promising way to reach precise personalized therapy in PDAC.

    abstract::Pancreatic cancer is currently one of the deadliest solid malignancies and pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. In the past decade, diagnostics and surgical techniques for PDAC have been evolving steadily; however, clinical outcomes of patients with PDAC have shown litt...

    journal_title:Cancer letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.canlet.2015.01.023

    authors: Xiang J,Liu L,Wang W,Xu H,Wu C,Xu J,Liu C,Long J,Ni Q,Yu X

    更新日期:2015-04-10 00:00:00

  • Reduction in NaCl-enhanced gastric carcinogenesis in rats fed a high-protein diet.

    abstract::The effect of a purified, high protein diet on enhanced gastric carcinogenesis induced by oral administration of NaCl was investigated in Wistar rats. Rats were fed on a purified diet with an equalized caloric content, containing 8% NaCl and 25% casein (normal protein diet), or 50% casein (high protein diet) after ora...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(97)00197-3

    authors: Tatsuta M,Iishi H,Baba M,Uehara H,Nakaizumi A,Iseki K

    更新日期:1997-06-24 00:00:00

  • Hemodynamic shear stress stimulates migration and extravasation of tumor cells by elevating cellular oxidative level.

    abstract::Cancer cells are shed into the blood stream and are exposed to hemodynamic shear stress during metastasis. It has been shown that shear stress can destroy circulating tumor cells (CTCs) both in vitro and in vivo. However, it remains unclear whether shear stress can modulate the properties and functions of tumor cells ...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2016.12.001

    authors: Ma S,Fu A,Chiew GG,Luo KQ

    更新日期:2017-03-01 00:00:00

  • Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.

    abstract::The regulator of G protein signaling 10 (RGS10) protein is a GTPase activating protein that accelerates the hydrolysis of GTP and therefore canonically inactivates G proteins, ultimately terminating signaling. Rheb is a small GTPase protein that shuttles between its GDP- and GTP-bound forms to activate mTOR. Since RGS...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2015.08.012

    authors: Altman MK,Alshamrani AA,Jia W,Nguyen HT,Fambrough JM,Tran SK,Patel MB,Hoseinzadeh P,Beedle AM,Murph MM

    更新日期:2015-12-01 00:00:00

  • Growth of mouse vaginal epithelial cells in culture: functional integrity of the estrogen receptor system and failure of estrogen to induce proliferation.

    abstract::Normal mouse vaginal epithelial cells isolated from ovariectomized ca. 40-day-old BALB/cCrg1 mice were purified by Percoll density gradient centrifugation and grown in primary culture using a collagen gel matrix and a serum-free complete medium. During the 9-day culture period, a 6-fold increase in cell number was obs...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(87)90124-8

    authors: Uchima FD,Edery M,Iguchi T,Larson L,Bern HA

    更新日期:1987-06-01 00:00:00

  • High expression rate of Tn antigen in metastatic lesions of uterine cervical cancers.

    abstract::The significance of altered expression of MN blood group antigens was examined by studies on the expressions of Thomsen-Friedenreich antigen (T antigen) and Tn antigen in primary and metastatic lesions of 29 human uterine cervical cancers. These antigens were measured by the avidin-biotin-peroxidase (ABC) method with ...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(93)90239-6

    authors: Hamada S,Furumoto H,Kamada M,Hirao T,Aono T

    更新日期:1993-11-01 00:00:00

  • Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland.

    abstract::Associations between lung cancer risk and common polymorphisms in the DNA repair genes xeroderma pigmentosum complementation group D (XPD), X-ray repair cross-complementing group 1 (XRCC1), XRCC3 and apurinic/apyrimidinic endonuclease/redox factor 1 were examined within a randomized clinical trial designed to determin...

    journal_title:Cancer letters

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1016/s0304-3835(02)00638-9

    authors: Misra RR,Ratnasinghe D,Tangrea JA,Virtamo J,Andersen MR,Barrett M,Taylor PR,Albanes D

    更新日期:2003-03-10 00:00:00

  • APAF-1 signaling in human melanoma.

    abstract::Acquired resistance to mechanisms of programmed cell death is one of the hallmarks of cancer. Human melanoma, in advanced stage, is hardly curable, due to development of several strategies that impair apoptosis induced by the death receptor and the mitochondrial pathways of apoptosis. Among these apoptosis escape stra...

    journal_title:Cancer letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.canlet.2005.06.034

    authors: Anichini A,Mortarini R,Sensi M,Zanon M

    更新日期:2006-07-18 00:00:00

  • Prognostic significance of tumor angiogenesis in primary fallopian tube cancer.

    abstract::Tumor angiogenesis has been found to be prognostically significant in many types of malignant tumors. We assessed tumor vascularity in 43 cases of histologically proven primary fallopian tube cancer, FIGO stage I-IV, using the highly specific endothelial cell marker CD34. Microvessel count was determined by counting C...

    journal_title:Cancer letters

    pub_type: 杂志文章,多中心研究

    doi:10.1016/s0304-3835(99)00104-4

    authors: Bancher-Todesca D,Rosen A,Graf A,Wasicky R,Hohlagschwandtner M,Rebhandl W,Heinze G,Breitenecker G,Gitsch G,Obermair A

    更新日期:1999-07-01 00:00:00

  • Nitrotyrosine in esophageal squamous cell carcinoma and relevance to p53 expression.

    abstract::We have examined the expression of nitrotyrosine, a marker of peroxynitrite formation, in 55 esophageal cancers by immunohistochemistry. Nitrotyrosine was detected in 21 of 55 (38.2%) esophageal cancers. Comparison of nitrotyrosine expression and the pathological findings showed that there was a significant associatio...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(00)00358-x

    authors: Kato H,Miyazaki T,Yoshikawa M,Nakajima M,Fukai Y,Tajima K,Masuda N,Tsutsumi S,Tsukada K,Nakajima T,Kuwano H

    更新日期:2000-05-29 00:00:00

  • BRCA1-2 mutations in breast cancer: identification of nine new variants of BRCA1-2 genes in a population from central Western Spain.

    abstract::We carried out a mutational analysis of BRCA1 and BRCA2 genes in 103 individuals from a population in Western Central Spain and we identified nine new variants: two truncating mutations in BRCA2 [2604C>A (Y792X), 8873del4], three missense mutations in BRCA2 [677A>G (H150R), 958G>A (D224N) and 3398A>G (K1057R], and fou...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2005.03.006

    authors: Salazar R,Cruz-Hernandez JJ,Sanchez-Valdivieso E,Rodriguez CA,Gomez-Bernal A,Barco E,Fonseca E,Portugal T,Gonzalez-Sarmiento R

    更新日期:2006-02-20 00:00:00

  • Phenotypically selective promotion of diethylnitrosamine-initiated altered hepatocyte foci by dietary phenobarbital or a topically applied coal-derived organic mixture in male and female rats.

    abstract::Relative frequencies of diethylnitrosamine (DEN)-initiated foci of altered hepatocytes appearing in response to promotion by either dietary phenobarbital or a topically applied coal-derived organic mixture (CDM) were investigated in male and female rats. The focus population was examined for two histochemical markers,...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(87)90155-8

    authors: Peraino C,Haugen DA,Carnes BA,Reilly CA Jr,Springer DL,Mahlum DD

    更新日期:1987-10-30 00:00:00

  • Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells.

    abstract::Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock progra...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2010.01.035

    authors: Jing H,Zhou X,Dong X,Cao J,Zhu H,Lou J,Hu Y,He Q,Yang B

    更新日期:2010-08-28 00:00:00

  • Transplacental effect of diethylstilbestrol in female rats.

    abstract::The effect of diethylstilbestrol propionate (DES; 1 mg/kg body wt. was studied in the female offspring of rats exposed subcutaneously on the 19th day of gestation. Examination of vaginal smears showed persistent estrus in adult rats treated prenatally with DES. Compensatory ovarian hypertrophy (COH) induced by hemicas...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/s0304-3835(79)80008-7

    authors: Napalkov NP,Anisimov VN

    更新日期:1979-02-01 00:00:00

  • Genistein potentiates the effect of arsenic trioxide against human hepatocellular carcinoma: role of Akt and nuclear factor-κB.

    abstract::Hepatocellular carcinoma (HCC) is a highly lethal malignancy mostly because of de novo and acquired resistance to conventional chemotherapy. Constitutive activation of Akt and nuclear factor-κB (NF-κB) represent major cellular abnormalities associated with both the pathogenesis and therapeutic resistance of HCC. The a...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/j.canlet.2010.10.022

    authors: Ma Y,Wang J,Liu L,Zhu H,Chen X,Pan S,Sun X,Jiang H

    更新日期:2011-02-01 00:00:00

  • P-glycoprotein expression by human colonic tumor cells influences the growth of tumor cells in vitro.

    abstract::The stability of P-glycoprotein expression by high and low expressing cells obtained by flow sorting from two cell lines established from colonic tumors was assessed. Low expressing cells rapidly recovered expression to a level that was comparable to that determined for uncloned cells. High expressing cells maintained...

    journal_title:Cancer letters

    pub_type: 杂志文章

    doi:10.1016/0304-3835(95)03838-n

    authors: Frommel TO

    更新日期:1995-08-01 00:00:00