Proteomic Profile Regulated by the Anticancer Peptide CIGB-300 in Non-Small Cell Lung Cancer (NSCLC) Cells

Rodríguez-Ulloa, Arielis; Ramos, Yassel; Gil, Jeovanis; Perera, Yasser; Castellanos‐Serra, Lila; García, Yairet; Betancourt, Lázaro; Besada, Vladimir; González, Luis Javier; Fernández-de-Cossío, Jorge; Sánchez, Aniel; Serrano, Joem M.; Fariña, Hernán G.; Alonso, Daniel F.; Acevedo, Boris; Padrón, Gabrìel; Musacchio, Andrea; Perea, Silvio E.

doi:10.1021/pr100728v

Cited by 25 publications

(21 citation statements)

References 76 publications

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“…Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis, mitochondrial metabolism, and ribosomal biogenesis, in agreement with the functional roles ascribed to B23/NPM and with a previous proteomic analysis [24]. Since the enrichment analysis was done at gene level, we further corroborated the impairment of these cellular processes using suitable molecular and cellular markers.…”

Section: Introductionsupporting

confidence: 90%

Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

et al. 2015

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B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES = 8.4, p < 0.001), mitochondrial ATP metabolism (ES = 2.5, p < 0.001), and ribosomal biogenesis (ES = 1.5, p < 0.05). The impairment of these cellular processes by CIGB-300 was corroborated at the molecular and cellular levels by Western blot (P-S6/P-4EBP1, translation), confocal microscopy (JC-1, mitochondrial potential), qPCR (45SrRNA/p21, ribosome biogenesis), and electron microscopy (nucleolar structure, ribosome biogenesis). Altogether, our findings provide new insights on the potential relevance of the CK2-mediated phosphorylation of B23/NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300.

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Section: Introductionsupporting

confidence: 90%

Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

et al. 2015

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“…Although paclitaxel and cisplatin are not direct substrates for this enzyme, both drugs require the activation of the MAP kinase pathway to exert their maximal cytotoxicity, which is prevented by high levels of GST-Pi. Moreover, at least three other proteins associated with drug resistance were clearly downregulated by CIGB-300 in NCI-H125 cells (15). Whether the synergistic/additive interaction patterns observed with the combination of CIGB-300 with cisplatin or paclitaxel may be explained by these molecular events require elucidation by further studies.…”

Section: Discussionmentioning

confidence: 95%

“…The first molecular clues that may explain the synergistic interaction with anticancer drugs in lung cancer cells were previously revealed by proteomics analysis of CIGB-300-treated NCI-H125 cells (15). In such studies, the peptide modulated an array of proteins associated with drug resistance and survival, which may favor the cytotoxic effect of several chemotherapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

“…However, considering the high degree of conservation for the CK2 phosphoaceptor domain, a multitarget effect may be anticipated (14). 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).…”

Section: Introductionmentioning

confidence: 99%

“…Of note, previous data from proteomics studies demonstrated that CIGB-300 modulates a group of proteins directly involved in anticancer drug resistance (15). Therefore, in this study, we evaluated the antiproliferative effect of CIGB-300 when combined with four different chemotherapeutics drugs in two model cell lines derived from lung and cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Perera

Toro

Gorovaya

et al. 2014

Molecular and Clinical Oncology

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Abstract. CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

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Characterization of low‐abundance species in the active pharmaceutical ingredient of CIGB‐300: A clinical‐grade anticancer synthetic peptide

Garay

Espinosa

Perera

et al. 2018

Journal of Peptide Science

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CIGB-300 is a first-in-class synthetic peptide-based drug of 25 amino acids currently undergoing clinical trials in cancer patients. It contains an amidated disulfide cyclic undecapeptide fused to the TAT cell-penetrating peptide through a beta-alanine spacer. CIGB-300 inhibits the CK2-mediated phosphorylation leading to apoptosis of tumor cells in vitro, and in vivo in cancer patients. Despite the clinical development of CIGB-300, the characterization of peptide-related impurities present in the active pharmaceutical ingredient has not been reported earlier. In the decision tree of ICHQ3A(R2) guidelines, the daily doses intake, the abundance, and the identity of the peptide-related species are pivotal nodes that define actions to be taken (reporting, identification, and qualification). For this, purity was first assessed by reverse-phase chromatography (>97%) and low-abundance impurities (≤0.27%) were collected and identified by mass spectrometry. Most of the impurities were generated during peptide synthesis, the spontaneous air oxidation of the reduced peptide, and the lyophilization step. The most abundant impurity, with no biological activity, was the full-length peptide containing Met transformed into a sulfoxide residue. Interestingly, parallel and antiparallel dimers of CIGB-300 linked by 2 intermolecular disulfide bonds exhibited a higher antiproliferative activity than the CIGB-300 monomer. Likewise, very low abundance trimers and tetramers of CIGB-300 linked by disulfide bonds (≤0.01%) were also detected. Here we describe for the first time the presence of active dimeric species whose feasibility as novel CIGB-300 derived entities merits further investigation.

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Proteomic Profile Regulated by the Anticancer Peptide CIGB-300 in Non-Small Cell Lung Cancer (NSCLC) Cells

Cited by 25 publications

References 76 publications

Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

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

Characterization of low‐abundance species in the active pharmaceutical ingredient of CIGB‐300: A clinical‐grade anticancer synthetic peptide

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