CIGB-300, a novel proapoptotic peptide that impairs the CK2 phosphorylation and exhibits anticancer properties both in vitro and in vivo

Abstract

Protein Kinase CK2 is a serine-threonine kinase frequently deregulated in many human tumors. Here, we hypothesized that a peptide binder to the CK2 phosphoacceptor site could exhibit anticancer properties in vitro, in tumor animal models, and in cancer patients. By screening a random cyclic peptide phage display library, we identified the CIGB-300 (formerly P15-Tat), a cyclic peptide which abrogates the CK2 phosphorylation by blocking recombinant substrates in vitro. Interestingly, synthetic CIGB-300 led to a dose-dependent antiproliferative effect in a variety of tumor cell lines and induced apoptosis as evidenced by rapid caspase activation. Importantly, CIGB-300 elicited significant antitumor effect both by local and systemic administration in murine syngenic tumors and human tumors xenografted in nude mice. Finally, we performed a First-in-Man trial with CIGB 300 in patients with cervical malignancies. The peptide was found to be safe and well tolerated in the dose range studied. Likewise, signs of clinical benefit were clearly identified after the CIGB-300 treatment as evidenced by significant decrease of the tumor lesion area and histological examination. Our results provide an early proof-of-principle of clinical benefit by using an anti-CK2 approach in cancer. Furthermore, this is the first clinical trial where an investigational drug has been used to target the CK2 phosphorylation domain.

Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity

“…In this article, we uncovered the putative mechanism of action for the novel proapoptotic peptide CIGB-300 (5,6,12). This peptide was developed to impair the tumor-exacerbated CK2 pathway by targeting the phosphoaceptor site on the substrate rather than the enzyme per se (3,4).…”

Pharmacological and safety evaluation of CIGB-300, a casein kinase 2 inhibitor peptide, administered intralesionally to patients with cervical cancer stage IB2/II

“…As a molecular targeted agent, CIGB-300 inhibits the CK2-mediated phosphorylation of the B23/ NPM nucleolar protein and this event lead to apoptosis in tumor cells. Furthermore, degradation of B23/NPM on CIGB-300-treated cells has been also documented in nonsmall cell lung cancer cells with great sensitivity toward CIGB-300 [10,11]. Therefore, the decrease on the B23/ NPM might be indicative of some clinical activity at the molecular level.…”

“…9 Molecular Oncology Laboratory, National University of Quilmes, Buenos Aires, Argentina. 10 ELEA Laboratories, Buenos Aires, Argentina. 11 ChemoFrance Division, ChemoFrance, Paris, France.…”

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

“…The antineoplastic effect of this peptide has been well documented in the preclinical setting in vitro and in vivo (13,17,18). In 2006, the peptide entered a phase I clinical trial on patients with HSILs, where safety and efficacy signs were registered (19).…”

“…Such a multitarget effect may better explain the diverse arrays of proteins and processes that appear to be modulated by CIGB-300 and its already established antiangiogenic effect (15,16). Of note, CIGB-300 exerts a broad antiproliferative effect on cell lines derived from breast, cervical, lung, colon and prostate cancer, while a robust antitumor effect was also observed in vivo in mouse models of cervical and lung cancer (13,17,18). In the clinical setting, CIGB-300 was investigated in a phase I clinical trial on high-grade squamous intraepithelial lesions (HSILs), establishing its safety and tolerability by local injection (19).…”