Abstract
BackgroundMulti-drug resistance and predisposition to metastasize are major clinical problems in cancer treatment. Malignant primary brain tumor and pancreatic cancer are two well-known examples of malignant tumors resistant to conventional therapies where aberrant EGFR-mediated and NF-κB signal transduction pathways are likely to play an important role. We have recently identified 1,3-Dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl] diben-zo(b,d) furan-2,7-diol (D11) as a potent and selective inhibitor of CK2 a serine/threonine protein kinase that modulates the aforementioned signaling cascades.MethodsHuman cancer cell lines (glioblastoma and pancreatic adenocarcinoma) resistant to conventional chemotherapeutic agents were incubated with increasing concentrations of D11 for variable amounts of time. Cell viability, cell death and effects on major signal transduction pathways deregulated in cancer cells were analyzed by ELISA, FACS and Western blot-based assays, respectively. Moreover, effects on cell migration and in cell protein-protein association were investigated by wound-healing and in situ proximity ligation assays, respectively.ResultsWe show here, that D11 treatment leads to i) significant caspase-mediated apoptotic cell death, ii) down-regulation of EGFR expression and iii) inhibition of NF-κB transcriptional activity. Furthermore, cell exposure to D11 results in impaired cell migration and correlates with reduced expression of the ion co-transporter and cell volume regulator Na+-K+-2Cl− (NKCC1).ConclusionsData reported here underline the therapeutic potential of D11 with respect to certain types of cancer that carry aberrant intracellular signaling cascades and/or exhibit sustained cell migration and suggest a new therapeutic strategy against chemotherapy resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0234-6) contains supplementary material, which is available to authorized users.
Highlights
Multi-drug resistance and predisposition to metastasize are major clinical problems in cancer treatment
The nuclear factor-κB (NF-κB) signaling pathway is often constitutively activated in cancer due to mutations in the genes coding for NF-κB isoforms or in those coding for proteins (e.g. IκBα) that control NF-κB activity [4, 6, 11]
We show that D11 treatment results in caspase-dependent activation of cell death, which correlates with increased activity of ROCK kinase
Summary
Multi-drug resistance and predisposition to metastasize are major clinical problems in cancer treatment. We have recently identified 1,3-Dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl] diben-zo(b,d) furan-2,7-diol (D11) as a potent and selective inhibitor of CK2 a serine/threonine protein kinase that modulates the aforementioned signaling cascades. Large-scale multi-dimensional analysis of clinical data has provided a detailed map of the major molecular alterations occurring during cancer development and led to two important observations: i) tumors originating from the same type of tissue or organ display significant differences with respect to genomic alterations and ii) tumors with different origin bear common. We have recently identified 1,3-Dichloro-6-[(E)-((4methoxyphenyl)imino)methyl] diben-zo(b,d) furan-2,7diol (referred to as D11) as a novel potent and selective inhibitor of protein kinase CK2 from a screening of 1600 compounds of the Diversity Set III from the DTP program of the NCI/NIH [17]. It regulates the NF-κB pathway by promoting IκB degradation and NF-κB phosphorylation that results in enhanced DNA binding and transcriptional activity of the latter [20,21,22,23]
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