Combined treatment of glibenclamide and CoCl2 decreases MMP9 expression and inhibits growth in highly metastatic breast cancer

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Abstract

Background

To observe the influence of combination treatment with glibenclamide and CoCl ₂ on the growth and invasiveness of TA2 breast cancer, and to detect the protein and mRNA expression of MMP9.

Methods

50 adult female TA2 mice were randomly divided into 5 groups including DMSO control, CoCl _2, glibenclamide, CoCl ₂ + glibenclamide and paclitaxel. All of these mice were inoculated with TA2 spontaneous breast cancer cells in the left groin. Nine days after inoculation the tumor could be palpated. Different treatments for each group were then subcutaneously administered near the tumors on the 9th and 14th days after injection. Tumor size was measured to determine the growth curve. All mice were sacrificed on the 18th day after initial inoculation and tumor tissues were collected. Some fresh tissues without necrosis were stored at −80°C for mRNA detection and the other tumor tissue was fixed with 10% formalin for H&E and immunohistochemical staining.

Results

The growth rate of tumor cells in the CoCl ₂ + glibenclamide group was lower than that seen in the other groups. On the 14th day, the average volume of tumor in the CoCl ₂ + glibenclamide group was the lowest and the difference has statistical significance ( P < 0.05), while the differences among the CoCl ₂, glibenclamide and paclitaxel had no statistical significance. The mean percentage of cells expressing MMP9 and PCNA was the lowest in the CoCl ₂ + glibenclamide group ( P < 0.05). MMP9 mRNA expression paralleled MMP9 protein expression in these groups ( P < 0.05).

Conclusions

Combined treatment with glibenclamide and CoCl ₂ inhibits TA2 spontaneous breast cancer growth and invasiveness with effects similar to paclitaxel.

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Cancer as a metabolic disease

Thomas Seyfried, Laura M Shelton (2010)

Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.

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Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.

Sumita Bhatta, Kathryn G. West, Ludmila Melnitchenko … (2006)

Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC(Ca-ATP) channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC(Ca-ATP) but not K(ATP) channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC(Ca-ATP) channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.

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CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2.

J Piret, Carine Michiels, Denis Mottet … (2002)

HIF-1 (hypoxia-inducible factor-1) is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF-1alpha and ARNT (aryl hydrocarbon receptor nuclear translocator). ARNT is constitutively expressed, whereas HIF-1alpha is targeted to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF-1alpha is stabilized and translocates to the nucleus, where it binds to ARNT. The active HIF-1 induces expression of various genes whose products play an adaptive role to the new conditions induced by hypoxia. Besides the role played by HIF-1 in the adaptation to hypoxia, recent data describe a possible role for HIF-1 in the modulation of apoptosis. According to some authors, hypoxia induces apoptosis. However, it has also been reported that hypoxia could protect cells against apoptotic cell death induced by various agents such as serum deprivation and incubation in the presence of chemotherapy agents. These contradictory data suggest that HIF-1 could display either a proapoptotic or an antiapoptotic role according to the conditions. In order to study how HIF-1 can modulate apoptosis, we studied whether hypoxia or cobalt chloride, a chemical inducer of HIF-1, could influence apoptosis induced by tert-butyl hydroperoxide (t-BHP), serum deprivation, or both in hepatoma cell line HepG2. HepG2 cells were incubated 8 hours under normoxia or hypoxia in the presence of t-BHP with or without CoCl2. CoCl2 reduced the apoptotic death of HepG2 cells induced by t-BHP and serum deprivation, as measured by DNA fragmentation. This effect was confirmed by measurement of the caspase activity. Moreover, hypoxia also prevented t-BHP- or serum deprivation-induced DNA fragmentation and caspase activation-however, to a lower extent than CoCl2. These different data suggest a possible antiapoptotic role of HIF-1. More experiments are needed to define if HIF-1 actually plays an active role in cell death protection and to determine the exact mechanism underlying this effect.

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Author and article information

Contributors

Zhe Rong

Li Li

Fei Fei

Lailong Luo

Yang Qu

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date Collection: 2013

Publication date (Electronic): 28 May 2013

Volume: 32

Issue: 1

Page: 32

Affiliations

[1 ]Department of Basic Medicine & Experimental Technology, Division of Clinical Medicine, Logistic University of Chinese People’s Armed Police Force, Tianjin 300162, P. R. China

[2 ]Department of Pathology, Anhui Medical University, Hefei, Anhui Province 230032, P. R. China

[3 ]Department of Neurosurgery, Logistic University Affiliated Hospital, Logistic University of Chinese People’s Armed Police Force, Tianjin 300162, P. R. China

Article

Publisher ID: 1756-9966-32-32

DOI: 10.1186/1756-9966-32-32

PMC ID: 3680297

PubMed ID: 23714264

SO-VID: 5a985085-7d6a-46f5-bf7e-2d8ae7f0b73f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 25 April 2013

Date accepted : 26 May 2013

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