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

Abstract

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.

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

“…(37). Other in vitro investigations, using combinations of CIGB-300 with chemotherapeutic agents including paclitaxel, doxorubicin, cisplatin, and 5-fluorouracil in lung and cervical cancer cell models, show promise for further clinical investigation (38). Paclitaxel displayed the strongest synergism with CIGB-300 in NCI-H125 and SiHa cell lines, with 5-fold less peptide being required to achieve an antiproliferative effect level of 94% in NCI-H125 cells.…”

“…Paclitaxel displayed the strongest synergism with CIGB-300 in NCI-H125 and SiHa cell lines, with 5-fold less peptide being required to achieve an antiproliferative effect level of 94% in NCI-H125 cells. With the same combination setting, the concentration of paclitaxel could be reduced more than 3,000-fold without compromising the final antiproliferative effect (38). Ongoing trials for optimization of CIGB-300 treatment and delivery approaches highlight its utility as an alternative to small-molecule ATP-competitive inhibitors for targeting CSNK2 in cancer (39).…”

Molecules that target nucleophosmin for cancer treatment: an update

“…CIGB-300 exerts a broad antiproliferative effect on cell lines derived from breast, cervical, lung, colon, prostate cancer and chronic lymphocytic leukemia (CLL) while a robust antitumour effect was also observed in vivo in mouse models of cervical and lung cancer as well as CLL [98, 103, 104]. Recently it was also observed that the concomitant administration of CIGB-300 and drugs like cisplatin, paclitaxel, doxorubicin or 5-fluorouracil cisplatin gives rise to synergic chemotherapeutic effects in lung and cervical cancer models [105]. …”

Cryptotanshinone inhibits lung tumor growth by increasing CD4+ T cell cytotoxicity through activation of the JAK2/STAT4 pathway

“…Lung cancer is a highly malignant disease and the incidence is increasing annually (1). With the enhancement and popularity of efforts aimed at educating individuals about not smoking, this incidence rate of smoking has shown a declining trend.…”

“…Foxp3 transforms primary CD4 + T cells into CD4 + regulatory T cells, and the normal expression of the gene is built around the premise that CD4 + regulatory T cells play a role (6). The Janus kinase 2/signal transducer and activator of transcription 4 (JAK2/STAT4) signaling pathway is activated continuously and abnormally activated in a variety of tumor tissues and cell lines, which promotes tumor growth, invasion, angiogenesis and metastasis (1). Increased activation of the the JAK2/STAT4 signaling pathway has been demonstrated in a variety of tumors, including stomach and liver cancer (2).…”