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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2020

01-12-2020 | Lymphoma | Research article

Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells

Authors: Mitsuki Tabata, Masanobu Tsubaki, Tomoya Takeda, Keisuke Tateishi, Katsumasa Tsurushima, Motohiro Imano, Takao Satou, Toshihiko Ishizaka, Shozo Nishida

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

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Abstract

Background

Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome. However, chemoresistance can lead to chemotherapy failure and very poor prognosis; thus, novel strategies are urgently required for patients with drug-resistant BL. To investigate the mechanisms underlying drug resistance in BL, we established drug-resistant BL cell lines: HS-Sultan/ADM (adriamycin-resistant), HS-Sultan/VCR (vincristine-resistant), HS-Sultan/DEX (dexamethasone-resistant), and HS-Sultan/L-PAM (melphalan-resistant).

Methods

Drug transporter and survival factor expression were investigated the using western blotting and real time polymerase chain reaction. Cell survival was analyzed by trypan blue dye exclusion method.

Results

The established cell lines acquired cross-resistance to adriamycin, vincristine, dexamethasone, and melphalan and exhibited 50% inhibitory concentration values 106-, 40-, 81-, and 45-fold higher than the parental cell lines, respectively. We found that protein and mRNA expression of MDR1 and Survivin were higher in drug-resistant BL cells than in the parent cells. Treatment with verapamil, an MDR1 inhibitor, or Survivin siRNA alongside each anti-cancer drug suppressed the proliferation of all drug-resistant BL cells. Src kinase activity was higher in all resistant cell lines than the parental cells; suppressing Src with dasatinib restored drug sensitivity by reducing MDR1 and Survivin expression.

Conclusions

MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.
Appendix
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Metadata
Title
Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells
Authors
Mitsuki Tabata
Masanobu Tsubaki
Tomoya Takeda
Keisuke Tateishi
Katsumasa Tsurushima
Motohiro Imano
Takao Satou
Toshihiko Ishizaka
Shozo Nishida
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-020-2879-8

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