Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Kawakami, Mariko; Kawakami, Koji; Puri, Raj K.

doi:10.1002/ijc.10778

Cited by 13 publications

(9 citation statements)

References 24 publications

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“…Complete inhibition of ETA-induced ssDNA formation and D4-GDI cleavage by Z-VAD-fmk suggests an essential role of the caspasedependent pathway in ETA-induced mast cell apoptosis. This finding is supported by others (7,42) who demonstrate caspase-3-like activities induced by immunotoxins or chimeric proteins with growth factors such as interleukin-13 (11,43). These chimeric products, however, may involve additional mechanisms such as Fc receptors (immunotoxins) or growth factor receptors such as interleukin-13 receptors and other factors, in addition to toxin-mediated effects.…”

Section: Figsupporting

confidence: 56%

“…Because of its potent cytotoxicity, ETA has been widely used to generate fusion proteins to kill target cells. For example, chimeric cytotoxins have been constructed by the fusion of growth factors or antibodies with the enzymatic region of ETA to specifically target and eliminate cancer cells, virally infected cells, or mast cells (7)(8)(9)(10)(11)(12). It is generally accepted that ETA is internalized by the cell surface receptor CD91 (the ␣2-macroglobulin receptor/low density lipoprotein receptor-related protein) (13) and asserts its cellular toxicity by blocking protein synthesis through ADP ribosylation of translation elongation factor 2 (14 -16).…”

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confidence: 99%

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Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism

Jenkins

Swiatoniowski

Issekutz

et al. 2004

Journal of Biological Chemistry

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Section: Figsupporting

confidence: 56%

mentioning

confidence: 99%

Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism

Jenkins

Swiatoniowski

Issekutz

et al. 2004

Journal of Biological Chemistry

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“…In addition, IL-13 cytotoxin has been shown to exhibit potent antitumor activity in vitro and in vivo in many tumor models, including SCC. 22,[26][27][28][29][30] To demonstrate the therapeutic efficacy of the IL-13 cytotoxin (IL13-PE38), which is composed of IL-13 and a truncated form of Pseudomonas exotoxin, [26][27][28] as an antitumor agent we assessed its cytotoxicity on primary cultures established from SCCs in TβRI COKO mice.…”

Section: Introductionmentioning

confidence: 99%

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Honjo

Bian²,

Kawakami³

et al. 2007

Cell Cycle

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We generated a mouse model with a conditional deletion of TGF-β signaling in the neurons by crossing TGF-β receptor I (TβRI) floxed mice with neurofilament-H (NF-H) Cre mice. 35% of F1 conditional knockout (COKO) mice developed spontaneous squamous cell carcinomas (SCCs) in periorbital and/or perianal regions. Transplantation of these tumors into athymic nude mice resulted in 62% tumorigenicity. To determine whether evasion of the immune response plays any role in this tumorigenesis, we analyzed the expression levels of receptors for interleukin-13 (mIL-13R), a key negative regulator of tumor immunosurveillance, and found that 33% of COKO tumors expressed the IL-13Ra2 chain. Primary cultures of the SCCs expressing IL-13Ra2 were sensitive to the cytotoxic effect of IL-13R-directed cytotoxin treatment. This is the first demonstration that loss of TβRI can lead to spontaneous tumor formation. These mice can serve as a unique mouse model of SCC to evaluate the tumorigenicity and effect of anti-cancer therapeutics.

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“…These molecules are found to be highly cytotoxic to tumor cells expressing IL-13R in vitro (1,7,8,10,18) and exhibit a potent antitumor activity in vivo in athymic nude mouse models of human cancers (19 -22). IL-13 cytotoxin mediated apoptotic and necrotic cell death in head and neck tumor in vitro and in vivo (23,24). Based on these preclinical results, Phase I/II clinical trials are currently ongoing to evaluate its safety, tolerability, and efficacy in patients with recurrent glioblastoma multiforme (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Accelerates Interleukin-13 Cytotoxin-Mediated Regression in Head and Neck Cancer Animal Model

Kawakami

Puri

2004

Clinical Cancer Research

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Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N -monomethyl-L-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N -monomethyl-L-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.

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Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways

Cited by 13 publications

References 24 publications

Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism

Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Nitric Oxide Accelerates Interleukin-13 Cytotoxin-Mediated Regression in Head and Neck Cancer Animal Model

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