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

Jl, Soriano-García; Lopez-Díaz, Ana M; Solares-Asteasuainzarra, M; Baladrón-Castrillo, I; Batista-Albuerne, N; García‐García, Inmaculada; González-Méndez, Lorena; Negrín, Yasser Perera; Cm, Valenzuela-Silva; Ap, Pedro; Ls, Quevedo-Sotolongo; Hernández-González, Ignacio; Jm, Silveira-Pablos; Chong-López, A; Df, Alonso; Re, Renault Jy Gómez; Perrin, P.; Sigman, Hugo; Gold, Stuart; Se, Perea-Rodríguez; Be, Acevedo-Castro; Herrera-Martínez, L; Pa, López-Saura

doi:10.14312/2052-4994.2013-25

Cited by 13 publications

(5 citation statements)

References 19 publications

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“…Contrary to conventional ATP-competitive inhibitors that target the catalytic subunits of CK2, CIGB-300 impairs CK2-mediated phosphorylation by direct binding to a conserved phosphoacceptor domain [32]. Previous preclinical and clinical studies have demonstrated the antineoplastic potential of CIGB-300 in solid tumors [33][34][35][36][37][38]. However, the exploration of this anti-CK2 peptide in hematological cancers is still limited [47].…”

Section: Discussionmentioning

confidence: 99%

“…CIGB-300 is a peptide chimera containing a cell-penetrating moiety and designed to impair CK2-mediated phosphorylation by binding to the substrate conserved phosphoacceptor sites [32]. This peptide exhibited pro-apoptotic and antitumor effects in different pre-clinical cancer models [33][34][35] and has been tested in Phase I/II clinical trials for the treatment of cervix and lung cancers [36][37][38]. Whereas CX-4945/silmitarsetib has been evaluated in a diversity of T-ALL studies [15,25,27,28], the anti-tumoral effects and mechanisms of action of CIGB-300 in this malignancy remain unaddressed.…”

Section: Introductionmentioning

confidence: 99%

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Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Perera

Melão

Ramón

et al. 2020

Cancers

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“…Such studies demonstrated that the peptide can interact with the protein kinase CK2α catalytic subunit and impair CK2 enzymatic activity in non-small cell lung cancer (NSCLC) and T-cell acute lymphoblastic leukemia (T-ALL) cell lines [33,34]. Concerning a CIGB-300 antineoplastic effect, the peptide has exhibited a strong pro-apoptotic and anti-tumor effect in pre-clinical cancer models [35,36] and has also been tested in Phase I/II clinical trials in patients with cervical cancer and a Phase I trial in patients with relapsed/refractory solid tumors [37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

et al. 2021

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Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy.

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“…Treatment with CIGB-300 significantly reduced the B23/nucleophosmin levels in tumor specimens. CIGB-300 meets potentialities to be tested in future trials in a neoadjuvant setting prior to chemoradiotherapy in cervical cancer [11] (Figure 2). …”

Section: Additional Advantage Of the Cyclic Peptidesmentioning

confidence: 99%

From Bench to Clinical Using a Combinatorial Screenings of Phage-Displayed Peptide Libraries

Vispo¹,

Cabrera²

2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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

Cited by 13 publications

References 19 publications

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

From Bench to Clinical Using a Combinatorial Screenings of Phage-Displayed Peptide Libraries

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