Marco de Bruyn - Academia.edu (original) (raw)

Papers by Marco de Bruyn

Sigma receptor (σR) ligands can enhance the anti-tumor actions of cytostatics. Previously, we hav... more Sigma receptor (σR) ligands can enhance the anti-tumor actions of cytostatics. Previously, we have shown that sub-toxic amounts of σR ligands, haloperidol or rimcazole, and TRAIL (a tumor-selective pro-apoptotic protein) synergistically kill human A375M melanoma cells. Although we established a caspase-dependent mechanism of synergy, the precise mechanism of interaction remained elusive. In this study, we assessed early metabolic responses in cultured and primary tumor or non-tumor cells in order to determine if tracer uptake reflects synergistic cell killing and can provide insight into underlying molecular events. Methods: A375M (human melanoma) and HUVEC (human umbilical cord endothelial) cells were incubated (24h) with 1) antiMCSP:TRAIL (0.1 µg/ml), 2) rimcazole (15 µM), 3) rimcazole + antiMCSP:TRAIL, 4) haloperidol (38 µM) or 5) haloperidol + antiMCSP:TRAIL. OC (primary ovarian carcinoma) was incubated (48h) with 1) antiEGFR:TRAIL (0.3 µg/ml), 2) rimcazole (23 µM) or 3) rimcazo...

Autophagy, 2015

Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC... more Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR (epidermal growth factor receptor)-targeted therapy. We uncovered that KRAS mutant (KRAS(mut)) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 (rLGALS9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rLGALS9 rapidly internalizes via early- and late-endosomes and accumulates in the lysosomal compartment. Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS(mut) CRC, but not in CRC with BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations (BRAF(mut)). In KRAS(mut) CRC, rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS(mut) cancer cells. Thus, rLGALS9 has potent antitumor activity towards refractory KRAS(mut) CRC cells that may be exploitable for therapeutic use.

Background: Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during... more Background: Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model.

Frontiers in Oncology, 2015

† Marco de Bruyn and Valerie R. Wiersma have contributed equally to this work.

Medicinal Research Reviews, 2013

In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) ... more In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) in health and disease. In normal physiology, Gal-9 seems to be a pivotal modulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations. Because these T-cell populations are associated with autoimmunity, inflammatory disease, and graft rejection, it was postulated that application of exogenous Gal-9 may limit pathogenic T-cell activity. Indeed, treatment with recombinant Gal-9 ameliorates disease activity in various preclinical models of autoimmunity and allograft graft rejection. In many solid cancers, the loss of Gal-9 expression is closely associated with metastatic progression. In line with this observation, treatment with recombinant Gal-9 prevents metastatic spread in various preclinical cancer models. In addition, various hematological malignancies are sensitive to apoptotic elimination by recombinant Gal-9. Here, we review the biology and physiological role of this versatile lectin and discuss the therapeutic potential of Gal-9 in various diseases, including autoimmunity, asthma, infection, and cancer.

Cancer Letters, 2013

Ideally, an immunotoxin should be inactive 'en route', acquire activity only after tumor cell sur... more Ideally, an immunotoxin should be inactive 'en route', acquire activity only after tumor cell surface binding and have no off-target effects towards normal cells. In this respect, antibody-based fusion proteins that exploit the tumor-selective pro-apoptotic death ligands sFasL and sTRAIL appear promising. Soluble FasL largely lacks receptor-activating potential, whereas sTRAIL is inactive towards normal cells. Fusion proteins in which an anti-tumor antibody fragment (scFv) is fused to sFasL or sTRAIL prove to be essentially inactive when soluble, while gaining potent anti-tumor activity after selective binding to a predefined tumor-associated cell surface antigen. Importantly, off-target binding by scFv:sTRAIL to normal cells showed no signs of toxicity. In this review, we highlight the rationale and perspectives of scFv:TRAIL/scFv:sFasL based fusion proteins for cancer therapy.

Neurobiology of Learning and Memory, 2007

A-kinase anchoring protein 150 (AKAP150) is a multi-enzyme signaling complex that coordinates the... more A-kinase anchoring protein 150 (AKAP150) is a multi-enzyme signaling complex that coordinates the action of PKA, PKC, and PP2B at neuronal membranes and synapses. We measured levels of AKAP150 protein in the hippocampus 6h after training mice in a contextual fear conditioning paradigm. In contextual fear conditioning mice learn to associate a context with a footshock presentation. Mice were divided

Sigma receptor (σR) ligands can enhance the anti-tumor actions of cytostatics. Previously, we hav... more Sigma receptor (σR) ligands can enhance the anti-tumor actions of cytostatics. Previously, we have shown that sub-toxic amounts of σR ligands, haloperidol or rimcazole, and TRAIL (a tumor-selective pro-apoptotic protein) synergistically kill human A375M melanoma cells. Although we established a caspase-dependent mechanism of synergy, the precise mechanism of interaction remained elusive. In this study, we assessed early metabolic responses in cultured and primary tumor or non-tumor cells in order to determine if tracer uptake reflects synergistic cell killing and can provide insight into underlying molecular events. Methods: A375M (human melanoma) and HUVEC (human umbilical cord endothelial) cells were incubated (24h) with 1) antiMCSP:TRAIL (0.1 µg/ml), 2) rimcazole (15 µM), 3) rimcazole + antiMCSP:TRAIL, 4) haloperidol (38 µM) or 5) haloperidol + antiMCSP:TRAIL. OC (primary ovarian carcinoma) was incubated (48h) with 1) antiEGFR:TRAIL (0.3 µg/ml), 2) rimcazole (23 µM) or 3) rimcazo...

Autophagy, 2015

Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC... more Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR (epidermal growth factor receptor)-targeted therapy. We uncovered that KRAS mutant (KRAS(mut)) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 (rLGALS9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rLGALS9 rapidly internalizes via early- and late-endosomes and accumulates in the lysosomal compartment. Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS(mut) CRC, but not in CRC with BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations (BRAF(mut)). In KRAS(mut) CRC, rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS(mut) cancer cells. Thus, rLGALS9 has potent antitumor activity towards refractory KRAS(mut) CRC cells that may be exploitable for therapeutic use.

Background: Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during... more Background: Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model.

Frontiers in Oncology, 2015

† Marco de Bruyn and Valerie R. Wiersma have contributed equally to this work.

Medicinal Research Reviews, 2013

In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) ... more In recent years, an important role has emerged for the glycan-binding protein Galectin-9 (Gal-9) in health and disease. In normal physiology, Gal-9 seems to be a pivotal modulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations. Because these T-cell populations are associated with autoimmunity, inflammatory disease, and graft rejection, it was postulated that application of exogenous Gal-9 may limit pathogenic T-cell activity. Indeed, treatment with recombinant Gal-9 ameliorates disease activity in various preclinical models of autoimmunity and allograft graft rejection. In many solid cancers, the loss of Gal-9 expression is closely associated with metastatic progression. In line with this observation, treatment with recombinant Gal-9 prevents metastatic spread in various preclinical cancer models. In addition, various hematological malignancies are sensitive to apoptotic elimination by recombinant Gal-9. Here, we review the biology and physiological role of this versatile lectin and discuss the therapeutic potential of Gal-9 in various diseases, including autoimmunity, asthma, infection, and cancer.

Cancer Letters, 2013

Ideally, an immunotoxin should be inactive 'en route', acquire activity only after tumor cell sur... more Ideally, an immunotoxin should be inactive 'en route', acquire activity only after tumor cell surface binding and have no off-target effects towards normal cells. In this respect, antibody-based fusion proteins that exploit the tumor-selective pro-apoptotic death ligands sFasL and sTRAIL appear promising. Soluble FasL largely lacks receptor-activating potential, whereas sTRAIL is inactive towards normal cells. Fusion proteins in which an anti-tumor antibody fragment (scFv) is fused to sFasL or sTRAIL prove to be essentially inactive when soluble, while gaining potent anti-tumor activity after selective binding to a predefined tumor-associated cell surface antigen. Importantly, off-target binding by scFv:sTRAIL to normal cells showed no signs of toxicity. In this review, we highlight the rationale and perspectives of scFv:TRAIL/scFv:sFasL based fusion proteins for cancer therapy.

Neurobiology of Learning and Memory, 2007

A-kinase anchoring protein 150 (AKAP150) is a multi-enzyme signaling complex that coordinates the... more A-kinase anchoring protein 150 (AKAP150) is a multi-enzyme signaling complex that coordinates the action of PKA, PKC, and PP2B at neuronal membranes and synapses. We measured levels of AKAP150 protein in the hippocampus 6h after training mice in a contextual fear conditioning paradigm. In contextual fear conditioning mice learn to associate a context with a footshock presentation. Mice were divided