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.