Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

El-Zawahry, Ahmed; McKillop, John; Voelkel‐Johnson, Christina

doi:10.1186/1471-2407-5-2

Cited by 66 publications

(38 citation statements)

References 22 publications

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“…However, a clinical phase I study with Apo2L/TRAIL in a single agent setting has been started in the fall of 2004 (A Ashkenazi, personal communication). Provided a hopefully positive outcome for this study, Apo2L/TRAIL could be another potential candidate for combination with DNA-damaging treatments (Rohn et al, 2001;Belka et al, 2003Belka et al, , 2004El-Zawahry et al, 2005).…”

Section: Discussionmentioning

confidence: 88%

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

et al. 2006

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We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

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Section: Discussionmentioning

confidence: 88%

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

et al. 2006

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“…Because c-FLIP is a well-known inhibitor of caspase 8 activation and its degradation following drug treatment releases caspase 8 for activation ( 23,24 ), we next determined whether FASN overexpression affects drug-induced degradation of c-FLIP using Western blot analysis. As shown in supplementary It has also been shown that doxorubicin increases PI3K-dependent AKT phosphorylation/activation as early as 1 h with a peak at 24 h ( 26 ).…”

Section: Fasn Overexpression Has No Effect On C-flip Level and Akt Acmentioning

confidence: 99%

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

Liu

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org in normal nonadipose tissues/cells. Cancer cells, however, synthesize more than 90% of their triacylglycerol de novo, requiring increased FASN expression ( 1 ). The important role of FASN in cancer cell proliferation/survival and its potential oncogenic function have been demonstrated in several previous studies ( 2-8 ).Overexpression of FASN has been associated with poor prognosis and higher risk of recurrence of human cancers of the breast ( 9-12 ) and prostate ( 13 ), as well as many other types of cancers ( 1 ), suggesting that increased FASN expression may also contribute to disease progression and treatment failure. In particular, FASN overexpression has been found in a drug-selected breast cancer cell line, and this elevation contributes to cellular resistance to Adriamycin (doxorubicin) and mitoxantrone in breast ( 14 ) and to gemcitabine in pancreatic cancer cells ( 15 ). However, the mechanism by which FASN contributes to drug resistance is currently unknown.In this study, we investigated the molecular mechanism of FASN-mediated drug resistance using FASN overexpression stable clones of MCF7 cells and found that FASN overexpression causes resistance to multiple anticancer drugs as well as to ␥ -irradiation via inhibiting treatmentinduced ceramide production, caspase 8 activation, and apoptosis. Further studies showed that FASN overexpression suppresses tumor necrosis factor (TNF)-␣ production, nuclear factor (NF)-B activation, and drug-induced activation of neutral sphingomyelinase (nSMase). Hence, FASN overexpression may cause drug resistance by inhibiting TNF-␣ expression, which in turn suppresses activation of NF-B and nSMase and, thus, reduced ceramide production, caspase 8 activation, and apoptosis.Abstract Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-␣ production and nuclear factor-B activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-␣ may play an important role in mediating FASN function in drug resistance. Mammalian FASN is a homo-dimer of a multifunctional protein of ‫ف‬ 270 kDa containing seven catalytic domains: ␤ -ketoacyl synthase, malonyl/acetyltransferase, dehydrogenase, enoyl reductase, ␤ -ketoacyl reductase, acyl carrier protein, and thioesterase . Under normal physiologi...

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“…This finding created great interest and suggested TRAIL or anti-DR5 antibodies, respectively, as potential anticancer drugs (Fulda and Debatin, 2004). Although TRAIL or DR5-antibodies showed only modest effects on experimental tumors, recent studies combining TRAIL with radiation or chemotherapeutic drugs, for example alkylphosphocholines or substances inducing DNAbreakage (Belka et al, 2001(Belka et al, , 2004Rohn et al, 2001;Jendrossek et al, 2002Jendrossek et al, , 2003El-Zawahry et al, 2005) revealed very effective induction of apoptosis and suggest that TRAIL or anti-DR5 antibodies might be used in combination with further chemotherapeutic drugs and/or irradiation.…”

Section: Introductionmentioning

confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAILmediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASMdeficient splenocytes fail to cluster DR5 in ceramideenriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C 16 -ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

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Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

Cited by 66 publications

References 22 publications

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

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