Changes in intracellular activation-related gene expression and induction of Akt contribute to acquired resistance toward nelarabine in CCRF-CEM cell line

Abstract

Drug resistance is a major problem in treatment with nelarabine, and its resolution requires elucidation of the underlying mechanisms. We established two nelarabine-resistant subclones of the human T-cell lymphoblastic leukemia cell line CCRF-CEM. The resistant subclones showed changes in the expression of several genes related to nelarabine intracellular activation and inhibition of apoptosis. Activation of the Akt protein upon nelarabine treatment was observed in both subclones. The combination treatment with nelarabine and PI3K/Akt inhibitors was shown to inhibit cell growth. Cross-resistance was observed with ara-C and not with vincristine, daunorubicin, or etoposide treatment. Thus, changes in the expression of cellular activation-related genes, inhibition of apoptosis, and induction of Akt may be involved in the development of nelarabine resistance in the CCRF-CEM cell model. The use of different classes of chemotherapeutic agents and combination therapy with PI3K/Akt pathway inhibitors may be used to overcome resistance to nelarabine.

Keywords:

• T-cell acute lymphoblastic leukemia
• drug resistance
• nelarabine
• combination therapy
• PI3K/Akt pathway

Acknowledgments

The authors would like to thank Ms. Emiko Miyahara for her technical assistance during the experiments. We wish to thank Joint Research Laboratory, Kagoshima University Graduate School of Medical and Dental Sciences, for the use of their facilities.

Disclosure statement

Almitra Rindiarti received financial support as a doctoral study scholarship from Otsuka Toshimi Scholarship Foundation.

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Additional information

Funding

This work was supported by a grant from Grant-in-Aid for Scientific Research (C), Japan [17K10117].