Cytotoxic efficacy of a novel dinuclear platinum(II) complex used with anti-MUC1 in human breast cancer cells

Gornowicz, Agnieszka; Kałuża, Zbigniew; Bielawska, Anna; Gabryel-Porowska, Halina; Czarnomysy, Robert; Bielawski, Krzysztof

doi:10.1007/s11010-014-2018-2

Cited by 20 publications

(19 citation statements)

References 27 publications

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“…In addition, the anti-MUC1 antibody GP1.4 decreased proliferation and migration of pancreatic cells by facilitating MUC1 internalization and inhibiting EGFR signaling 45 . The combined treatment with anti-MUC1 antibody GP1.4 and platinum (II) complex induced better cytotoxic and proapoptotic effects in breast cancer cell line 35 , 46 . A MUC1 antibody, C595, in association with docetaxel, significantly decreased tumor growth in a xenograft model of ovarian cancer by augmenting apoptosis and necrosis 47 .…”

Section: Discussionmentioning

confidence: 95%

A Mucin1 C-terminal Subunit-directed Monoclonal Antibody Targets Overexpressed Mucin1 in Breast Cancer

Wu¹,

Kim²,

Kim³

et al. 2018

Theranostics

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Background: Mucin1 (MUC1) is a highly glycosylated transmembrane protein that has gained attention because of its overexpression in various cancers. However, MUC1-targeted therapeutic antibodies have not yet been approved for cancer therapy. MUC1 is cleaved to two subunits, MUC1-N and MCU1-C. MUC1-N is released from the cell surface, making MUC1-C a more reasonable target for cancer therapy. Therefore, we produced a monoclonal antibody (anti-hMUC1) specific to the extracellular region of MUC1-C and evaluated its effects in vitro and in vivo.Methods: We produced a monoclonal antibody (anti-hMUC1) using a purified recombinant human MUC1 polypeptide and our novel immunization protocol. The reactivity of anti-hMUC1 was characterized by ELISA, western blotting and immunoprecipitation analyses. The localization of the antibody in the breast cancer cells after binding was determined by confocal image analysis. The effects of the antibody on the growth of cells were also investigated. We injected anti-hMUC1 and performed in vivo tracing analysis in xenograft mouse models. In addition, expression of MUC1 in tissue sections from patients with breast cancer was assessed by immunohistochemistry with anti-hMUC1.Results: The anti-hMUC1 antibody recognized recombinant MUC1 as well as native MUC1-C protein in breast cancer cells. Anti-hMUC1 binds to the membrane surface of cells that express MUC1 and is internalized in some cancer cell lines. Treatment with anti-hMUC1 significantly reduced proliferation of cells in which anti-hMUC1 antibody is internalized. Furthermore, the anti-hMUC1 antibody was specifically localized in the MUC1-expressing breast cancer cell-derived tumors in xenograft mouse models. Based on immunohistochemistry analysis, we detected significantly higher expression of MUC1 in cancer tissues than in normal control tissues. Conclusion: Our results reveal that the anti-hMUC1 antibody targets the extracellular region of MUC1-C subunit and may have utility in future applications as an anti-breast cancer agent.

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Section: Discussionmentioning

confidence: 95%

A Mucin1 C-terminal Subunit-directed Monoclonal Antibody Targets Overexpressed Mucin1 in Breast Cancer

Wu¹,

Kim²,

Kim³

et al. 2018

Theranostics

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“…In our latest studies we also proved that combination treatment with chemotherapeutic agents plus monoclonal antibody against MUC1 resulted in higher cytotoxicity and better proapoptotic effect than monotherapy [ 46 , 47 ], thus suggesting that combination strategy results in better efficacy than the use of chemotherapeutics alone.…”

Section: Discussionmentioning

confidence: 98%

Anticancer Effect of a Novel Octahydropyrazino[2,1-a:5,4-a′]diisoquinoline Derivative and Its Synergistic Action with Nigella sativa in Human Gastric Cancer Cells

Czajkowska

Gornowicz

Pawłowska

et al. 2017

BioMed Research International

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Many studies have shown that naturally occurring compounds may support prevention and treatment of various diseases, including cancer. Pharmacological investigations revealed a wide spectrum of Nigella sativa biological activities. Combining natural compounds together with synthetic drugs may increase the anticancer activity and limit severe side effects of such a treatment and may be an alternative to monotherapy. The aim of the study was to evaluate the cytotoxic and proapoptotic effects of a novel octahydropyrazino[2,1-a:5,4-a′]diisoquinoline derivative and its effect in combination with Nigella sativa seed oil or extract in human gastric cancer cells (AGS). Etoposide was used as a reference. Our studies proved that combination strategy based on novel octahydropyrazino[2,1-a:5,4-a′]diisoquinoline derivative (OM-90) with Nigella sativa seed oil or extract represents the strongest efficacy in AGS cancer cells as compared to monotherapy and combined treatment with Nigella sativa seed oil or extract together with etoposide. Such a combination also leads to the activation of mitochondrial pathway, which plays a significant role in molecular mechanism of induction of apoptosis by these compounds.

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“…Our preliminary studies showed that Pt 2 (4-ethylpyridine) 4 (berenil) 2 (Pt12) used together with anti-MUC1 antibody is more cytotoxic than Pt12 alone or cisplatin with anti-MUC1 in breast cancer MCF-7 and MDA-MB-231 cells. The anti-proliferative effect of Pt12 with anti-MUC1 was dependent on the estrogen receptor status of the breast cancer cells [ 20 ]. Pt12 with anti-MUC1 was proved to be a stronger inhibitor of collagen biosynthesis in breast cancer cells compared to Pt12 alone and cisplatin with anti-MUC1.…”

Section: Discussionmentioning

confidence: 99%

“…ELISA’s kits were purchased from Uscn Life Science Inc. and BioVendor. The chemical synthesis and structure of Pt12 was presented in publication [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…Our preliminary studies where we checked the combined effects of a monoclonal antibody against MUC1 used together with a novel dinuclear platinum complex (Pt12) showed high anti-proliferative properties and a strong cytotoxic activity in two breast cancer cell lines (MCF-7 and MDA-MB-231). This effect was much stronger than the treatment with anti-MUC1, cisplatin, Pt12, or cisplatin in the presence of anti-MUC1 [ 20 ]. A key element of the research is to understand the molecular mechanisms of apoptosis induced by anti-MUC1 in combination with the new platinum complex in MDA-MB-231 cells.…”

Section: Introductionmentioning

confidence: 99%

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The combined treatment with novel platinum(II) complex and anti-MUC1 increases apoptotic response in MDA-MB-231 breast cancer cells

et al. 2015

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New strategy of cancer’s targeting treatment is combining monoclonal antibodies with chemotherapeutic agents. An important goal of targeted therapy appears to be a transmembrane glycoprotein type I—mucin 1 (MUC1), which is overexpressed in tumors of epithelial origin, especially in breast cancer. The goal of the study was to check the effect of monoclonal antibody against MUC1 with novel platinum(II) complex (Pt12) on selected aspects of apoptosis in human MDA-MB-231 breast cancer cells. The number of apoptotic and necrotic cells was measured using annexin V binding assay. The decrease of mitochondrial membrane potential (MMP) and DNA fragmentation was analyzed. Finally, the influence of novel platinum(II) complex (Pt12) used with anti-MUC1 on the concentration of selected markers of apoptosis such as Bax, caspase-8, -9, and caspase-3 was performed using ELISA. The results from combined treatment were compared with those obtained using monotherapy. In our study, we proved that anti-MUC1 used in combination with Pt12 strongly induced apoptosis in MDA-MB-231 breast cancer cell line. The effect was stronger than treatment with Pt12, cisplatin, anti-MUC1, and anti-MUC1 used with cisplatin. We also observed the highest decrease of MMP and the strongest DNA fragmentation after such a combined treatment. The results obtained from ELISA showed increased concentration of Bax, caspases-8, -9, -3 compared to monotherapy. Our study proved that Pt12 together with anti-MUC1 strongly induced apoptosis in estrogen-negative breast cancer cell line (MDA-MB-231). The apoptosis may go through extrinsic pathway associated with caspase-8 as well as intrinsic pathway connected with caspase-9.

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Cytotoxic efficacy of a novel dinuclear platinum(II) complex used with anti-MUC1 in human breast cancer cells

Cited by 20 publications

References 27 publications

A Mucin1 C-terminal Subunit-directed Monoclonal Antibody Targets Overexpressed Mucin1 in Breast Cancer

A Mucin1 C-terminal Subunit-directed Monoclonal Antibody Targets Overexpressed Mucin1 in Breast Cancer

Anticancer Effect of a Novel Octahydropyrazino[2,1-a:5,4-a′]diisoquinoline Derivative and Its Synergistic Action with Nigella sativa in Human Gastric Cancer Cells

The combined treatment with novel platinum(II) complex and anti-MUC1 increases apoptotic response in MDA-MB-231 breast cancer cells

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