Midkine inhibitor (iMDK) induces apoptosis of primary effusion lymphoma via G2/M cell cycle arrest

Mikinori Ueno; Ryusho Kariya; Sittithumcharee Gunya; Kodcharat Cheevapruk; Seiji Okada

doi:10.1016/j.leukres.2022.106826

Midkine inhibitor (iMDK) induces apoptosis of primary effusion lymphoma via G2/M cell cycle arrest

Leuk Res. 2022 May:116:106826. doi: 10.1016/j.leukres.2022.106826. Epub 2022 Mar 12.

Authors

Mikinori Ueno¹, Ryusho Kariya², Sittithumcharee Gunya³, Kodcharat Cheevapruk⁴, Seiji Okada⁵

Affiliations

¹ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Graduate School of Fisheries and Environmental Studies, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
² Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
³ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
⁴ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
⁵ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan. Electronic address: okadas@kumamoto-u.ac.jp.

PMID: 35316715
DOI: 10.1016/j.leukres.2022.106826

Abstract

Primary effusion lymphoma (PEL) is an aggressive B-cell non-Hodgkin lymphoma in immunocompromised individuals such as AIDS patients. PEL shows a poor prognosis (median survival time < 6 months) compared with other AIDS-related lymphomas, and is generally resistant to conventional treatments. Novel drugs for PEL treatment are required. Midkine inhibitor (iMDK) was previously found to suppress midkine protein expression. Interestingly, iMDK suppressed cell proliferation in PEL cell lines in a time- and dose-dependent manner, regardless of midkine gene expression. We examined the mechanism of iMDK on PEL. Importantly, iMDK strongly induced cell cycle arrest at the G2/M phase within 12 h of incubation and suppressed the p-CDK1 protein level, which is associated with the cell cycle checkpoint at G2/M, resulting in mitotic catastrophe with observation of multipolar division. After mitotic catastrophe, iMDK-treated PEL showed apoptosis with caspase-3, - 8, and - 9 activation at 24 h incubation. However, iMDK showed no effects on viral protein-activated signaling pathways such as JAK-STAT, PI3K-Akt and NF-κB, and HHV-8/KSHV gene expression in PEL. These results indicate that iMDK is a novel CDK1 inhibitor and a promising lead compound for PEL chemotherapy treatment.

Keywords: AIDS; Apoptosis; Cell cycle; Midkine inhibitor (iMDK); Primary effusion lymphoma (PEL).

Publication types

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

MeSH terms

Apoptosis
G2 Phase Cell Cycle Checkpoints
Herpesvirus 8, Human*
Humans
Lymphoma, Primary Effusion* / drug therapy
Lymphoma, Primary Effusion* / metabolism
Lymphoma, Primary Effusion* / pathology
Midkine / pharmacology
Phosphatidylinositol 3-Kinases / pharmacology
Phosphatidylinositol 3-Kinases / therapeutic use

Substances

Midkine