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Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers

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Abstract

The current study aims to evaluate the hepatoprotective and antitumor efficacy of doxycycline, as an matrix metalloproteases-9 (MMP-9) inhibitor, in an in vivo model of hepatocellular carcinoma (HCC). HCC was induced experimentally by thiocetamide (200 mg/kg) in rats that were treated with doxycycline (5 mg/kg for 16 weeks). Tumor severity was evaluated by measuring α-fetoprotein (AFP) levels, histopathologically by investigating liver sections stained with hematoxylin/eosin and assessing the survival rate. Liver homogenates were used for the measurements of MMP-9, fascin and hepatic heparan sulfate proteoglycan (HSPG) levels. Oxidative stress markers [malonaldehyde (MDA) and glutathione] as well as fibroblast growth factor-2 (FGF-2) gene expression were also among the assessed indicators. HCC in human and animal samples showed significant elevation in the levels of MMP-9 (231.7, 90 %), fascin (33.17, 140 %), as well as FGF-2 gene expression (342 % in animal samples; all respectively), associated with a significant decrease in hepatic HSPG level. Treatment of rats with doxycycline increased the animal survival rate (90 %) and decreased serum AFP level. Moreover, doxycycline ameliorated fibrosis and the induced massive hepatic tissue breakdown. It also restored the integrity of hepatic HSPGs and showed a magnificent inhibitory effect of tumor invasion cascade by significantly reducing the activities of MMP-9 (42 %) and fascin (50 %), as well as reducing the gene expression of FGF-2 (85.7 %). Furthermore, the antioxidant impact of doxycycline was evidenced by the significant elevation in glutathione level and depressing MDA level. To this end, doxycycline, proved promising hepatoprotective and antitumor activity and opens, thereby, a new horizon against vascular migration ability of the tumor cells.

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Abbreviations

HCC:

Hepatocellular carcinoma

ECM:

Extracellular matrix

MMPs:

Matrix metalloproteases

HS:

Heparan sulfate

HSPGs:

Heparan sulfate proteoglycans

HSGAGS:

Heparan sulfate glucosaminoglycans

FGF-2:

Fibroblast growth factor-2

ROS:

Review of systems

AFP:

α-Fetoprotein

PBS:

Phosphate buffer saline

MDA:

Malonaldehyde

ALT:

Alanine aminotransferase

cDNA:

Complementary DNA

Ct:

Threshold cycle

ELISA:

Enzyme-linked immunosorbent assay

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

H/E:

Hematoxylin and eosin

IHC:

Immunohistochemistry

i.p.:

Intraperitoneal

MDA:

Malondialdehyde

rpm:

Revolution per min

RT-PCR:

Real-time polymerase chain reaction

SEM:

Standard error of the mean

DAB:

3,3′-Diaminobenzidine

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Authors and Affiliations

  1. Dept. of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Misr International University, 28km Cairo-Ismailia Road, Cairo, 18111, Egypt

    Mohammed A. F. Elewa & Mona F. Schaalan

  2. Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Mohammed A. F. Elewa, Mohammed M. Al-Gayyar & Mamdouh M. El-Shishtawy

  3. Dept. of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia

    Mohammed M. Al-Gayyar

  4. Dept. of Microbiology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Khaled H. Abd El Galil

  5. Oncology Center, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt

    Mohamed A. Ebrahim

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  1. Mohammed A. F. Elewa
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  2. Mohammed M. Al-Gayyar
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Elewa, M.A.F., Al-Gayyar, M.M., Schaalan, M.F. et al. Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers. Clin Exp Metastasis 32, 479–493 (2015). https://doi.org/10.1007/s10585-015-9721-6

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