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Glucocorticoids attenuate the sensitivity of glucocorticoid-resistant lymphoid cells to doxorubicin via reduction in OCTN2

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Abstract

Glucocorticoid (GC) resistance is associated with poor response to the following chemotherapy in lymphoid malignancies, such as lymphoma and leukemia. However, it remains unclear whether GCs interfere with the cytotoxic effects of anti-cancer drugs on GC-resistant cells. In this study, we examined whether GCs affected the sensitivities to vincristine (VCR)/doxorubicin (DOX) and the expression of drug transporters in GC-resistant cells. The dexamethasone (DEX)/prednisolone (PSL)-resistant lymphoid and non-lymphoid cell lines Raji and HL60 were cultured with DEX for 7 days and then treated with VCR or DOX for 3 days. Seven days of DEX treatment increased the IC50s of both VCR and DOX in Raji cells but not in HL60 cells. The mRNA and protein expression levels of organic cation/carnitine transporter (OCTN) 2, one of the drug uptake transporters expressed in both cell lines, were decreased only in Raji cells. When Raji cells were cultured with PSL, the IC50 of DOX but not VCR increased as the expression of OCTN2 decreased. No significant increases in efflux transporter expression were induced by DEX or PSL. When siRNA against OCTN2 was introduced into Raji cells, the IC50 of DOX but not VCR increased significantly. These data suggested that both DEX and PSL decreased the sensitivity of the DEX/PSL-resistant Raji cells to DOX, a change that was at least partially due to reductions in OCTN2. Thus, the continuous usage of GCs may interfere with the effects of chemotherapy on GC-resistant lymphoid cells.

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Acknowledgements

We would like to thank Ms. Michiko Anzai (Fukushima Medical University, Fukushima, Japan) for providing technical assistance.

Funding

This study was funded by grants from the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (C) MO23591400 to Y.S. and MO24590325 to J.K.

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Authors and Affiliations

  1. Department of Pediatrics, Fukushima Medical University, Fukushima, Japan

    Mitsuko Akaihata & Mitsuaki Hosoya

  2. Department of Pediatrics, Aichi Medical University Hospital, Nagakute, Japan

    Mitsuko Akaihata

  3. Center for Medical Education and Career Development, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan

    Yayoi Shikama

  4. Department of Pharmacology, Fukushima Medical University, Fukushima, Japan

    Yayoi Shikama, Tomoyuki Ono & Junko Kimura

  5. Department of Cardiovascular, Fukushima Medical University, Fukushima, Japan

    Yoshiyuki Matsumoto

Authors
  1. Mitsuko Akaihata
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  2. Yayoi Shikama
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  3. Yoshiyuki Matsumoto
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  4. Tomoyuki Ono
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  5. Junko Kimura
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  6. Mitsuaki Hosoya
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Contributions

MA analyzed cytotoxicity, expression of transporters, effects of siRNA, and YS designed and integrated the study. TO and YM contributed to flow cytometric analyses and cytotoxicity assay. JK and MH supervised the study design and data analyses.

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Correspondence to Yayoi Shikama.

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Akaihata, M., Shikama, Y., Matsumoto, Y. et al. Glucocorticoids attenuate the sensitivity of glucocorticoid-resistant lymphoid cells to doxorubicin via reduction in OCTN2. Mol Cell Biochem 459, 49–59 (2019). https://doi.org/10.1007/s11010-019-03549-0

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