Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells

Wińska, Patrycja; Widło, Łukasz; Skierka, Katarzyna; Krzyśko, Alicja; Koronkiewicz, Mirosława; Cieśla, Jarosław M.; Cieśla, Joanna; Bretner, Maria

doi:10.21873/anticanres.13499

Cited by 11 publications

(12 citation statements)

References 37 publications

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“…Since it has been shown previously that the TBBi derivative [ 11 , 31 ], as well as 5-FU [ 32 ], can affect cell cycle progression of breast cancer cells, the influence of 5-FU in combination with either 14B or CX-4945 on cell cycle progression was tested after 48 and 72 h of treatment in MDA-MB-231 cells. The cell cycle distribution profiles after treatment with each compound used separately and in two different combinations were determined by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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“…In ALL cells, a combined treatment with methotrexate and CX-4945 synergistically inhibited cell proliferation, blocked cell cycle progression in the G2/M phase and promoted the activation of caspases 3/7 [40]. The anti-tumour activity of methotrexate is brought about by inhibition of dihydrofolate reductase (DHFR), as well as of other enzymes involved in nucleotide synthesis.…”

Section: Acute Lymphoblastic Leukaemiamentioning

confidence: 99%

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

et al. 2020

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Background Protein kinase CK2 inhibition has long been considered as an attractive anti-cancer strategy based on the following considerations: CK2 is a pro-survival kinase, it is frequently over-expressed in human tumours and its over-expression correlates with a worse prognosis. Preclinical evidence strongly supports the feasibility of this target and, although dozens of CK2 inhibitors have been described in the literature so far, CX-4945 (silmitasertib) was the first that entered into clinical trials for the treatment of both human haematological and solid tumours. However, kinase inhibitor monotherapies turned out to be effective only in a limited number of malignancies, probably due to the multifaceted causes that underlie them, supporting the emerging view that multi-targeted approaches to treat human tumours could be more effective. Conclusions In this review, we will address combined anti-cancer therapeutic strategies described so far which involve the use of CX-4945. Data from preclinical studies clearly show the ability of CX-4945 to synergistically cooperate with different classes of anti-neoplastic agents, thereby contributing to an orchestrated anti-tumour action against multiple targets. Overall, these promising outcomes support the translation of CX-4945 combined therapies into clinical anti-cancer applications.

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“…In many previous in vitro studies, tumour cells displayed growth inhibition mediated by CK2 inhibition. Studies have also shown reduced clonogenic survival following radiation in vitro and enhanced antitumor effects in vivo in some tumour models, suggesting a strong and promising radiosensitization potential for CK2 inhibiting agents (7)(8)(9)14).…”

Section: Discussionmentioning

confidence: 99%

In VivoEvaluation of Combined CK2 Inhibition and Irradiation in Human WiDr Tumours

Zwicker

Hauswald

Weber

et al. 2021

In Vivo

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Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells

Cited by 11 publications

References 37 publications

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

In VivoEvaluation of Combined CK2 Inhibition and Irradiation in Human WiDr Tumours

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