4,5,7‐trisubstituted indeno[1,2‐ b ]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue FEBS Open Bio Année : 2022

4,5,7‐trisubstituted indeno[1,2‐ b ]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

Résumé

Highly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials - CX-4945. In this study we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydro-indeno[1,2-b]indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549 and LNCaP tumor cell lines analogous to CX-4945 (>75% inhibition at 20 µM) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nM) compared to CX-4945 (119.3 nM). This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC50 = 25 nM (5a-2) and 3.7 nM (CX-4945)]. Examination of the effects of both CK2 inhibitors on cancer cells using live cell imaging revealed notable differences. Whereas CX-4945 showed a stronger pro-apoptotic effect on tumor cells, 5a-2 was more effective in inhibiting tumor cell migration. Our results showed that 49% of intracellular CX-4945 was localized in the nuclear fraction, whereas 71% of 5a-2 was detectable in the cytoplasm. The different subcellular distribution, and thus the site of CK2 inhibition, provide a possible explanation for the different cellular effects. Our study indicates that investigating CK2-inhibition-mediated cellular effects in relation to the subcellular sites of CK2 inhibition may help to improve our understanding of the preferential roles of CK2 within different cancer cell compartments.

Dates et versions

hal-03471998 , version 1 (09-12-2021)

Identifiants

Citer

Robin Birus, Ehab El‐awaad, Laurens Ballentin, Faten Alchab, Dagmar Aichele, et al.. 4,5,7‐trisubstituted indeno[1,2‐ b ]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects. FEBS Open Bio, 2022, 12, pp.394-411. ⟨10.1002/2211-5463.13346⟩. ⟨hal-03471998⟩
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