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A historical overview of protein kinase PKR… was not affected and was not necessary for the induction of
apoptosis in either breast or colon cancer cells. In addition,
tumour cells where p53 is mutated, considering that more the efficacy of Bozepinib was improved when combined
than 50% of colon tumours are deficient in p53 activity. with IFNa cytokine, which enhanced Bozepinib-induced
These results, taken together, provide evidence that PKR is apoptosis with involvement of protein kinase PKR (Figure
a key molecular target of 5-FU with potential relevance in 5). Moreover, we reported for the first time that, in
the clinical use of this drug (Figure 5), (154). A method of combined therapy, IFNa induces a clear process of
obtaining useful data to assess and predict the response to autophagosome formation. Finally, we observed that a
treatment with pyrimidine analogues has been protected by minor population of caspase 3-deficient MCF-7 breast
international patent (155). My contribution in this field cancer cells persisted during long-term treatment with
was as corresponding author of published data in Plos One lower doses of Bozepinib and the Bozepinib/IFNa
journal in 2011 and the main inventor of the patent. combination. Curiously, this population showed ß-
Moreover, we have recently published a patent review of galactosidase activity and a percentage of cells arrested in
5-FU derivates from 2012 to 2014 and their implications S phase, suggesting that tumour cells enter in senescence,
for standard and novel therapies in Expert Opinion on more evidently so in cells treated with the Bozepinib/IFNa
Therapeutic Patents journal (157). I am currently the combination than in cells treated with Bozepinib or IFNa
principal investigator of two projects funded by the alone. Considering the resistance of some cancer cells to
Andalusian regional government and the Carlos III conventional chemotherapy, these data suggested that
Institute of Health (ISCIII) whose main objective is to combinations enhancing the diversity of the cell death
analyse the biomarker potential of PKR in patients with outcome might succeed in delivering more effective and
colon cancer treated with therapies based on 5-FU drugs. less toxic chemotherapy (158).
4.1.c. Novel antitumour drugs with high capacity to induce Given the great potential exhibited by Bozepinib, we
eIF2a phosphorylation and cell death by apoptosis: have recently looked into its mechanism of action with
Bozepinib, a promising drug against cancer stem cells, very interesting results (159). Bozepinib shows selectivity
induces PKR-mediated apoptosis and synergises with IFN on cancer cells and an inhibitory effect over kinases
involved in carcinogenesis, proliferation, and
Dr Campos, Dr Marchal, Dr Aranega and co-workers angiogenesis. The cytotoxic effects of Bozepinib were
have a long history designing and researching new observed in both breast and colon cancer cells expressing
antitumour drugs that are more effective and less toxic different receptor patterns. Bozepinib inhibited HER-2
than currently standard cancer chemotherapy. My (human epidermal growth factor receptor 2) signalling
contribution to the group actually directed by Dr Marchal pathway and JNK (c-Jun-N terminal kinase) and ERKs
has helped determine the effectiveness of various drugs to (extracellular signal regulated kinases) kinases. In
induce the phosphorylation of eIF2a and/or PKR-mediated addition, Bozepinib has an inhibitory effect on AKT
apoptosis. Moreover, my experience with IFN has (protein kinase B) and VEGF (vascular endothelial growth
contributed to create a new line of research in the group factor) together with anti-angiogenic and anti-migratory
that aims to enhance the effectiveness of these novel drugs activities. Interestingly, Bozepinib inhibited both mammo-
in combination with biological therapies like interferons, and colonospheres formation regulating genes related to
among others. stem properties such as c-MYC, ß-CATENIN, SOX2 and
GLI-3 hedgehog-signalling repressor ,suggesting activity
The most studied drug by our group is called Bozepinib against cancer stem-like cells (Figure 5). Finally,
[(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5- Bozepinib shows in vivo anti-tumour and anti-metastatic
tetrahydro-4,1- benzoxazepin-3-yl]-9H-purine], which was efficacy in xenotransplanted nude mice without presenting
designed by the group directed by Dr Campos at the sub-acute toxicity. These findings support the need for
University of Granada (Figure 6), (157). Bozepinib is a further studies on the therapeutic potential of Bozepinib
potent antitumour compound that is able to induce for cancer patients and were recently published in the
apoptosis in breast cancer cells, as we published in 2011, Oncotarget journal under my leadership as corresponding
showing a 50% inhibitory concentration (IC50) of 0.166 author (159).
µM against the MDA-MB-231 human breast
adenocarcinoma cell line and inducing high levels of Also designed by the group lead by Dr Campos, other
apoptosis in tumour cells without acute toxicity in mice purines-derived compounds with antitumour efficacy that
(157). My contribution in 2013 as corresponding author we have characterised as potent inducers of eIF2a
and last author of the data published in the Drug Design, phosphorylation and apoptosis include the (R,S)-
Development and Therapy journal showed that Bozepinib Benzofused 1,5-Oxatiepine moiety tethered to purines
also has antitumour activity in colon cancer cells, showing compounds, the (RS)-9-(2,3-dihydro-1,4-benzoxaheteroin-
inhibitory concentration (IC50) values 50% lower than 2- ylmethyl)-9H-purines agents, and several
those described for breast cancer cells, and suggesting enantiospecific heterocycles linked to purines (160-162).
great potential for this synthetic drug in the treatment of
cancer (158). We identified PKR as a target of Bozepinib,
being upregulated and activated by the drug. However, p53
@Real Academia Nacional de Farmacia. Spain 157
