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. 2019 Feb 7:2019:8670398.
doi: 10.1155/2019/8670398. eCollection 2019.

Tyrosine Kinase Inhibitor Imatinib Mesylate Alters DMBA-Induced Early Onco/Suppressor Gene Expression with Tissue-Specificity in Mice

Péter Attila Gergely  1 , Balázs Murnyák  2 , János Bencze  3 , Andrea Kurucz  4 , Timea Varjas  5 , Katalin Gombos  6 , Tibor Hortobágyi  2   7
Affiliations

Tyrosine Kinase Inhibitor Imatinib Mesylate Alters DMBA-Induced Early Onco/Suppressor Gene Expression with Tissue-Specificity in Mice

Péter Attila Gergely et al. Biomed Res Int. .

Abstract

Tyrosine kinases play crucial roles in cellular development and tumorigenesis. Tyrosine kinase inhibitors (TKIs) are effective and widely used drug molecules in targeted cancer therapies. Altered expressions of protooncogenes and tumor suppressor genes after DMBA (7,12-dimethylbenz[a]anthracene) treatment have been described as early markers of tumor induction; however their tissue-specific effects remain still unclear. Our study was aimed at examining the short-term possible antineoplastic and chemopreventive effects of a TKI compound (imatinib mesylate) on a DMBA-induced mouse tumor model. In addition, we also investigated the tissue-specific expressions of Hras, Kras, Myc, and Trp53 genes in the brain, bone marrow, spleen, liver, abdominal lymph nodes, thymus, lungs, and kidneys, respectively. 24 hours after the imatinib mesylate injection, we observed significant Kras downregulation in the bone marrow and lung of the DMBA-treated mice. Moreover, the mRNA expression of Myc was also found to be decreased significantly in the spleen. Interestingly, while Trp53 expression was significantly increased in the lung, it was decreased in the other tissues. However, there was also a tendency in the decreased Myc level in the bone marrow, brain, kidneys, lungs, and lymph nodes and in the decreased Hras level in the bone marrow, kidneys, and lungs, although no significant differences were observed. Our findings indicate rapid tissue-specific impact of imatinib mesylate on DMBA-induced gene expression in vivo, supporting the chemopreventive potential of imatinib mesylate in cancer.

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Figures

Figure 1
Figure 1
Experimental design. Six- to eight-week-old (n=36) conventionally raised NMRI inbred mice were divided randomly into three sets: the negative control group was i.p. treated with the vehicle (corn oil) (1st set, n=12), the positive control group (2nd set, n=12) was treated i.p. with a 20 mg/kg body weight dose DMBA (7,12-dimethylbenz[a]anthracene), and the experimental group (3rd set, n=12) was treated i.p. with 10 mg/kg imatinib mesylate and 20 mg/kg DMBA. Animals were autopsied 24 hours after treatment, and organs were dissected and stored for further analysis.
Figure 2
Figure 2
Heat map of gene expression patterns compared to the negative control. Blue boxes represent negative (down) regulation, while red boxes indicate positive (up)regulation of the gene expression.
Figure 3
Figure 3
Gene expression pattern of experimental groups in different organs. ∗ p<0,05.
Figure 4
Figure 4
A gene-gene interaction network presenting the correlation among the fold regulation of Kras, Hras, Myc, and Trp53 genes in the represented organs and their predicted interactions with 10 functionally related genes. The 10 correlated genes were obtained using the GeneMania application of Cytoscape; level of significance: ∗ (p < 0.05).
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