CIGB-552 has antitumor effects in vitro and in
vivo
The studies of anticancer activity of CIGB-552 were performed usingin vitro culture systems as well as clinically relevant in
vivo models, as is shown in figure 2. We began with the demonstration
of a selective antiproliferative activity in several cancer cell lines.
We demonstrated that CIGB-552 has powerful antiproliferative and
cytotoxic effects compared to its precursor peptide L-2. In this assays,
we evaluated the effect of the peptide on non-tumor cell lines where the
IC50 was higher respect to tumor cells. These
differences suggest the selectivity of this peptide to malignant cells.
The IC50 values observed in tumor cell lines suggest a
tumor type-dependent pattern of sensitivity
(Fernandez Masso et al., 2013).
Since apoptosis often occurs as a consequence of a cell cycle blockade,
we checked whether the cytotoxicity of L-2 was mediated by an alteration
of the cell division cycle. Analyses by flow cytometry of tumor cells
treated with L-2, showed the absence of the G2/M peak and the
accumulation of cells in S phase. Recently, we demonstrated that this
difference is caused by the internalization mechanism of the peptide
(Vallespi et al., 2010).
The in vivo therapy on solid tumors was a subsequent phase in the
proof of concept of CIGB-552 as an anticancer drug (Figure 2). In our
institute, we developed a murine model of tumor CT-26. This model was
used to study the administration route and the dosage regimen for the
treatment. Firstly, we demonstrated that the subcutaneous administration
of CIGB-552 led to a significant reduction of tumor growth compared to
the group treated with saline solution. After two week of treatment, the
tumor volume was decreased and this behavior was observed until the end
of the study (Vallespi et al., 2014).
Therefore, this in vivo study demonstrated that subcutaneous
administration of CIGB-552 was able to inhibit the 50% of tumor growth
injecting the peptide once a week, during 2 weeks. In collaboration with
an EPO-Berlin institute, we further evaluated the effect of a
subcutaneous administration of CIGB-552 in a xenograft model of human
colon cancer HT-29. In this mouse model, we analyzed the body weight as
an indicator of tolerability. As occurs in the syngeneic CT26 model, the
peptide showed a significant reduction of tumor volume compared with the
control group. All mice of groups treated with CIGB-552 keep the body
weight during the study, indicating safety and tolerability. This study
included a group treated with Oxaliplatin, a standard drug in the
therapy of colorectal cancer. Oxaliplatin induced a significant
inhibition of tumor growth, but this effect was accompanied by a severe
loss of body weight and two deaths probably due to its high toxicity
(Vallespi et al., 2014).
The mechanisms involved in the reduction of tumor growth in response to
CIGB-552 were evaluated in both murine syngeneic and human xenograft
models. In vivo , the groups treated with CIGB-552 exhibit
induction of apoptosis in the tumor and a decrease of microvessels
density (Vallespi et al., 2014). The
resistance to programed cell death and the sustained angiogenesis are
included in a group of properties called hallmarks of cancer, a set of
functional capabilities acquired during the multistep development of
human tumors. Thus, the antitumor mechanism of the peptide CIGB-552 is
associated with proteins and signaling pathways that trigger apoptosis
inhibit the proliferation and induce the reduction of blood vessels
formation.
Monolayers of tumor cells cultivated in vitro and mouse
xenografts implanted with those cells, have been the standard toolkit to
cancer biologists for decades. However, the need for better and more
clinically predictive models of human cancer is imminent. Spontaneous
cancer in pet dogs is considered an attractive model to study the
efficacy of drug candidates to cancer therapy
(Rowell, McCarthy, & Alvarez, 2011).
Cancers in affective animals such as pet dogs are characterized by
histological features similar to human cancer, tumor growth over long
periods, inter-individual and intra-tumor heterogeneity, the development
of recurrent or resistant diseases, and metastasis to relevant distal
sites (Hawai et al., 2013). Based on
that, we evaluated the safety, tolerability and antineoplastic effect of
CIGB-552 in tumor-bearing dogs. In this study, our group keeps the same
dosage regimen used by subcutaneous route in mouse models. The treatment
with CIGB-552 had not any negative effect on total leukocytes, do not
affect the levels of liver transaminases or hemoglobin during the study
(Vallespi et al., 2017). Interesting, the
white blood count return to normal levels after completing the study,
which suggest that treatment with the peptide do not induce leucopenia,
a common issue in chemotherapy regimens. The dogs enrolled into the
study showed a tumor regression (> 50 %), demonstrating a
stabilization of the disease (Vallespi et
al., 2017).
Altogether, these preclinical results validate the peptide CIGB-552 as a
potent antiproliferative and antitumor drug which mechanism is related
with the inhibition of various hallmarks of cancer. In addition, the
subcutaneous administration of CIGB-552 is safe and successful as an
anticancer treatment at least, at preclinical level.