Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway

Yiying Zhu; Zhangxun Zhao; Minggao Xue; Dan Wang; Guifeng Su; Xiaoman Ju; Qihong Yang; Shaohua Zhang; Dongmei Fan; Huifang Zhu; Min Yu; Yan Li; Lingmei Kong; Hongyu Zhou

doi:10.1016/j.bbrc.2023.03.062

Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway

Biochem Biophys Res Commun. 2023 Jun 4:659:10-19. doi: 10.1016/j.bbrc.2023.03.062. Epub 2023 Apr 1.

Authors

Yiying Zhu¹, Zhangxun Zhao², Minggao Xue³, Dan Wang³, Guifeng Su¹, Xiaoman Ju², Qihong Yang², Shaohua Zhang¹, Dongmei Fan², Huifang Zhu⁴, Min Yu³, Yan Li¹, Lingmei Kong⁵, Hongyu Zhou⁶

Affiliations

¹ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Life Science, Yunnan University, Kunming, 650091, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
² State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
³ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Life Science, Yunnan University, Kunming, 650091, China.
⁴ Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
⁵ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Life Science, Yunnan University, Kunming, 650091, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: [email protected].
⁶ School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, Yunnan, China. Electronic address: [email protected].

PMID: 37030020
DOI: 10.1016/j.bbrc.2023.03.062

Abstract

The activating receptor natural killer group 2D (NKG2D) expressed by Natural killer (NK) cells functions as a "master-switch" in governing the awakening status of NK cells. The NKG2D-mediated cytotoxicity has been declared to be related with the expression levels of NKG2D ligands (NKG2DLs) expressed on tumor cells. Therefore, selective induction of NKG2DLs could be a reliable approach to enhance the efficacy of NK cell-mediated immunotherapy. Our existing study demonstrated that Ciclopirox Olamine (CPX), an off-patent antifungal agent, effectively elevated the expression of NKG2DLs on leukemia cells and sensitized leukemia cells to NK-cell mediated cytolysis. Induction of ROS production and AKT phosphorylation by CPX is essential for the up-regulation of NKG2DLs expressions. Inhibition of AKT by using AKT inhibitor MK2206 decreased both NKG2DLs expressions and NK cell cytotoxicity. These data indicated that increased sensitivity of CPX-treated leukemia cells to NK cell cytolysis was attributed to higher NKG2DLs expressions, resulting from activated AKT signaling pathway. Our findings support the ongoing development of CPX as an anti-tumor agent and suggest its promising immunotherapeutic value in the medication of leukemia.

Keywords: Ciclopirox olamine; Immunotherapy; NKG2D ligands; Natural killer cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Ciclopirox / metabolism
Ciclopirox / pharmacology
Humans
Killer Cells, Natural / metabolism
Leukemia* / drug therapy
Leukemia* / metabolism
NK Cell Lectin-Like Receptor Subfamily K / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction

Substances

Proto-Oncogene Proteins c-akt
Ciclopirox
NK Cell Lectin-Like Receptor Subfamily K