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Chelerythrine, a novel small molecule targeting IL-2, inhibits melanoma progression by blocking the interaction between IL-2 and its receptor

Published:1 May 2023 DOI: 10.1016/j.lfs.2023.121559 PMID: 36893941
Okki Cho , Joong-Woon Lee , Han-Sol Kim, Young-Jin Jeong, Tae-Hwe Heo

Abstract

Aims

In this study, we investigated the inhibition of IL-2 activity and anticancer efficacy of chelerythrine (CHE), a natural small molecule that targets IL-2 and inhibits CD25 binding, and elucidated the mechanism underlying the action of CHE on immune cells.

Main methods

CHE was discovered by competitive binding ELISA and SPR analysis. The effect of CHE on IL-2 activity was evaluated in CTLL-2, HEK-Blue reporter and immune cells, and in ex vivo generation of regulatory T cells (Treg cells). The antitumor activity of CHE was evaluated in B16F10 tumor-bearing C57BL/6 or BALB/c nude mice.

Key findings

We identified that CHE, which acts as an IL-2 inhibitor, selectively inhibits the interaction between IL-2 and IL-2Rα and directly binds to IL-2. CHE inhibited the proliferation and signaling of CTLL-2 cells and suppressed IL-2 activity in HEK-Blue reporter and immune cells. CHE prevented the conversion of naive CD4+ T cells into CD4+CD25+Foxp3+ Treg cells in response to IL-2. CHE reduced tumor growth in C57BL/6 mice but not in T-cell-deficient mice, upregulated the expression of IFN-γ and cytotoxic molecules, and limited Foxp3 expression. Furthermore, the combination of CHE and a PD-1 inhibitor synergistically increased antitumor activity in melanoma-bearing mice and almost completely regressed the implanted tumors.

Significance

We found that CHE, which targets IL-2 and inhibits its binding to CD25, exhibits T cell-mediated antitumor activity and that combination therapy with CHE and PD-1 inhibitor induced synergistic antitumor effects, suggesting that CHE may be a promising anticancer agent for melanoma monotherapy and combination therapy.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Chelerythrine 34316-15-9 C21H18NO4+ 255 suppliers $40.00-$2395.30
Chelerythrine 34316-15-9 C21H18NO4+ 255 suppliers $40.00-$2395.30
Chelerythrine 34316-15-9 C21H18NO4+ 255 suppliers $40.00-$2395.30
Chelerythrine 34316-15-9 C21H18NO4+ 255 suppliers $40.00-$2395.30

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