Combination of Human Fas (CD95/Apo-1) Ligand with Adriamycin Significantly Enhances the Efficacy of Antitumor Response

Liu, Zhongchen; Liu, Ruizhen; Qiu, Jianxian; Yin, Ping; Luo, Fanghong; Su, Jinhua; Li, Wenzhu; Chen, Caixia; Fan, Xueli; Zhang, Jiakai; Zhuang, Guohong

doi:10.1038/cmi.2009.23

Cited by 13 publications

(7 citation statements)

References 31 publications

(34 reference statements)

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“…Here, we demonstrate that DOX sensitizes tumors to NK and T‐cell‐mediated killing via augmented TRAIL signaling. Several different chemotherapy agents have recently been shown to sensitize tumors to TRAIL‐mediated killing . We and others have demonstrated that the proteasome inhibitor bortezomib can sensitize tumors to NK cell‐mediated killing via augmented TRAIL signaling .…”

Section: Discussionmentioning

confidence: 92%

Doxorubicin sensitizes human tumor cells to NK cell‐ and T‐cell‐mediated killing by augmented TRAIL receptor signaling

Wennerberg

Sarhan

Carlsten

et al. 2013

Intl Journal of Cancer

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Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.Several studies have demonstrated that intratumoral infiltration of T cells and NK cells correlates with favorable prognosis in patients with cancer.

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Section: Discussionmentioning

confidence: 92%

Doxorubicin sensitizes human tumor cells to NK cell‐ and T‐cell‐mediated killing by augmented TRAIL receptor signaling

Wennerberg

Sarhan

Carlsten

et al. 2013

Intl Journal of Cancer

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“…41,48,49 We asked whether the FAS-ligand promotes drug-induced apoptosis in neoplastic MCs. In these experiments we found that the FAS-ligand per se does not induce growth inhibition or apoptosis in neoplastic MCs.…”

Section: Effects Of Epigenetic Drugs On Neoplastic Mast Cells 4249mentioning

confidence: 99%

5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand

Ghanim

Herrmann

Heller

et al. 2012

Blood

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IntroductionSystemic mastocytosis (SM) is a myeloid neoplasm characterized by pathologic accumulation of mast cells (MCs) in one or more extracutaneous organs. 1,2 Indolent and aggressive variants of SM have been described. [1][2][3][4][5] In most patients, the transforming KIT mutation D816V is detectable independent of the category of SM. [6][7][8] Patients with indolent SM (ISM) have an excellent prognosis with normal or near-normal life expectancy. [1][2][3][4][5]9,10 In patients with aggressive SM (ASM) and mast cell leukemia (MCL), the prognosis is grave, [1][2][3][4][5]9,10 and responses to conventional drugs and most targeted drugs are poor. [1][2][3][4]9,[11][12][13][14][15] During the past few years, several attempts have been made to define new molecular targets in neoplastic MCs and to establish new treatment concepts for these patients. 16,17 Abnormal DNA methylation and histone-acetylation are frequently observed in various neoplasms and supposedly contribute to disease evolution and drug resistance. [18][19][20] In hematologic malignancies, epigenetic abnormalities have been reported in acute and chronic leukemias as well as in myelodysplastic syndromes (MDS). [21][22][23] Especially in patients with MDS, abnormal methylation of the genome has been described. 21,22 Correspondingly, epigenetically active drugs such as 5-azacytidine and 5-aza2Јdeoxycytidine (decitabine) reportedly act as antineoplastic agents in these patients. [23][24][25] More recent data suggest that demethylating agents also exert beneficial effects in patients in whom neoplastic cells exhibit myeloproliferative and myelodysplastic features, such as chronic myelomonocytic leukemia (CMML), and sometimes even in patients with advanced myeloproliferative neoplasms (MPN). 26,27 Advanced SM is a myeloid neoplasm that often presents with myeloproliferative features and sometimes with bone marrow (BM) dysplasia. [1][2][3][4][5] In addition, advanced SM may coexist with MDS (SM-MDS), CMML, or a JAK2-mutated MPN. 28 However, so far, no data on the effects of demethylating agents on neoplastic cells in advanced SM or SM-AHNMD are available. In addition, little is known about methylation patterns in neoplastic MCs. We explored the effects of 2 widely used demethylating agents, 5-azacytidine and decitabine, on growth and survival of neoplastic MCs, and examined the mechanism(s) of action of these drugs. MethodsDrugs, monoclonal antibodies, and other reagents PKC412 (midostaurin) was kindly provided by Dr J. Roesel and Dr P. W. Manley (Novartis). 5-azacytidine, decitabine, recombinant human FASligand, and propidium iodide (PI) were purchased from Sigma-Aldrich, Submitted September 27, 2011; accepted February 29, 2012. Prepublished online as Blood First Edition paper, March 21, 2012; DOI 10.1182 DOI 10. /blood-2011 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertis...

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“…This is probably the reason why only in a few cases the use of a single treatment may lead to full success, while the most promising results arise from the use of combined therapies. A promising study with recombinant soluble FasL protein shows that combined administration with the chemotherapeutic drug adriamycin exhibits a synergistic apoptotic effect on hepatocellular carcinoma cells, both in vitro and subcutaneously in vivo [160]. The resistance of many tumor cells to Fas-mediated apoptosis may also compromise the potential success of the bispecific antibodies approach.…”

Section: Combination Of Distinct Approaches To Improve Therapymentioning

confidence: 99%

Targeting the Fas/FasL signaling pathway in cancer therapy

Villa‐Morales

Fernández‐Piqueras

2012

Expert Opinion on Therapeutic Targets

139

102

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Combination of Human Fas (CD95/Apo-1) Ligand with Adriamycin Significantly Enhances the Efficacy of Antitumor Response

Cited by 13 publications

References 31 publications

Doxorubicin sensitizes human tumor cells to NK cell‐ and T‐cell‐mediated killing by augmented TRAIL receptor signaling

Doxorubicin sensitizes human tumor cells to NK cell‐ and T‐cell‐mediated killing by augmented TRAIL receptor signaling

5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand

Targeting the Fas/FasL signaling pathway in cancer therapy

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