Conclusions and future perspectives
CIGB-552 is a “first-in class” antitumor peptide developed by a series
of modifications from a structural motif present in the antimicrobial
protein LALF. This peptide in capable of penetrate inside the cell to
interact with different target proteins among which COMMD1 has been
identified. This pleotropic protein regulates the stability and activity
of several intracellular, endosomal and transmembrane proteins,
regulating a variety of biological processes. It has been described to
participate in the termination of NF-κB signalling and in the negative
regulation of SOD1, among other molecular events. CIGB-552 acting
through COMMD1, is able of induce oxidative stress and trigger apoptosis
in cancer cells and is effective, safe an tolerable in different animal
models of cancer including mice and dogs, what makes it a promising
candidate to cancer therapy. In fact this peptide drug is already in
clinical trials and has concluded recently the phase I study, which
demonstrated an overall positive effect in patients with no toxicity or
side effects.
In spite of that, the potential of CIGB-552 is still under evaluation.
Recent studies have revealed new findings about COMMD1 that could expand
the therapeutic applications of this peptide. Fedoseienko et al .
demonstrated that nuclear COMMD1 decreased protein expression of the DNA
repair gene BRCA1 and the apoptosis inhibitor BCL2 in
ovarian cells A-2780, conferring sensitivity to Cisplatin
(Fedoseienko et al., 2016). In addition,
they demonstrated through tissue micro-arrays that nuclear expression of
COMMD1 is associated with an improved response to chemotherapy. This
information supports the idea of the use of CIGB-552 in combined therapy
with other chemotherapeutic drugs, to improve antitumor effect and
reduce toxicity. In the same way, Yeh et al examined the association of
COMMD1 with stemness. The downregulation of COMMD1 amplifies
stemness-associated property of cancer cells
(Yeh et al., 2016), suggesting that
CIGB-552 could target cancer steam cells, which are involved in tumor
re-emergence, metastasis and multidrug resistance. Furthermore, COMMD1
has been reported as a negative regulator of the hypoxia inducible
factor 1 (HIF-1), which is implicated in tumor angiogenesis and
metastasis (van de Sluis et al., 2009;
van de Sluis et al., 2010), thus, this
could be another cancer-associated process modulated by CIGB-552.
Interestingly, in accordance with this hypothesis the peptide reduced
microvessel density in vivo in our CT-26 tumor mouse model.
CIGB-552 differentially modulates genes and proteins involved in key
signaling pathways of cancer cells such as NFκB, hypoxia, apoptosis and
inflammation. The recovery of COMMD1 levels by CIGB-552 negatively
regulates the NFκB activity in absence or presence of inflammatory
cytokines. Therefore, the molecular mechanism described for CIGB-552
validate its pharmacological use in chronic diseases such as human
cancer, by inhibiting inflammation, tumor angiogenesis and stemness
process or even in certain inflammatory conditions such as colitis and
colitis-related cancer, Inflammatory Bowel Disease, Crohn’s Disease
among others. Furthermore, CIGB-552 could be used in combination
regimens with non-steroidal anti-inflammatory drugs (NSAID),
antineoplastic agents and other target therapies. Substantial evidence
indicates that aspirin and related NSAIDs have potential as
chemopreventive/therapeutic agents (Drew,
Cao, & Chan, 2016; Patrignani &
Patrono, 2016). However, these drugs cannot be universally recommended
for prevention purposes due to their potential side-effect profiles.
Stark et al have demonstrated that Aspirin inhibits the transcriptional
activity of NFκB through stabilization of COMMD1 in colon cancer cells
(O’Hara et al., 2014;
Thoms et al., 2010). The intervention of
CIGB-552 in combination with Aspirin could mediate an improved effect
and could reduce the clinical dose of both drugs in cancer therapy. The
constitutive activation of NF-κB is one of the resistance mechanisms to
antineoplastic treatments. The inhibition of NF-κB activity by CIGB-552
could be an attractive strategy to sensitize tumors to antineoplastic
agents, reducing the doses of drugs and providing a better life quality
for patients.
Increasing evidence is pointing out COMMD1 as an attractive molecular
target involved in a variety of human disorders. CIGB-552 as a
biotechnological product that accumulate this protein and potentiate its
intracellular effect, represent an interesting candidate not only for
cancer therapy, but also to other metabolic diseases in which COMMD1 is
implicated. For example, the research group of Fedoseienko et al. has
also studied the role of COMMD1 in atherosclerosis. The localization of
COMMD1 in the endosome is critical for Low Density Lipoprotein Receptor
(LDLR) recycling and cholesterol levels in mice
(Bartuzi et al., 2016). Likewise,
Drevillon et al demonstrate that COMMD1 modulates the activity and
surface expression of the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) in epithelial cells, an activity that is down-regulated
in cystic fibrosis patients (Drevillon et
al., 2011). In line with this, CIGB-552 could be a therapeutical
alternative to atherosclerosis and cystic fibrosis, two human disorders
that do not possess a current effective treatment. The molecular
evidence and experimental data discussed throughout this review reveal
the peptide CIGB-552 as an interesting, effective and versatile drug
that could be developed as a novel anti-inflammatory and anticancer
drug, which could be effective for different human chronic conditions.