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Journal of Nippon Medical School

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Methylation of PLK-1 Potentially Drives Bendamustine Resistance in Leukemia Cells

Toshikazu Itabashi1, Takahiro Ueda1, Ryohei Fukunaga1, Takeshi Asano2 and Yasuhiko Itoh1

1Department of Pediatrics, Nippon Medical School, Tokyo, Japan
2Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan


Background: Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin's lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics.
Methods: Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry.
Results: Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells.
Conclusions: Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.

J Nippon Med Sch 2024; 91: 162-171

Keywords
bendamustine hydrochloride, leukemia, drug resistance, PLK-1, MDR1

Correspondence to
Takeshi Asano, Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan
july1364@nms.ac.jp

Received, August 20, 2023
Accepted, October 4, 2023