Abstract
BackgroundCurrent 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).MethodsDrug 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.ResultsThe 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.ConclusionsMDR1 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.
Highlights
Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome
Drug sensitivity of established adriamycin, vincristine, dexamethasone, and melphalan-resistant BL cell lines We found that our established resistant cell lines, HSSultan/ADM, HS-Sultan/VCR, HS-Sultan/DEX, and HS-Sultan/L-PAM, showed similar proliferation to the parental HS-Sultan cells; administration with adriamycin, vincristine, dexamethasone, and melphalan did not induced cell death in HS-Sultan/ADM, HS-Sultan/VCR, HS-Sultan/DEX, and HS-Sultan/L-PAM cells, but induced cell death in HS-Sultan cells (Fig. 1a)
Expression of Multiple drug resistance 1 (MDR1) and Survivin mRNA levels were elevated in all resistant cell lines than in the parental cells (Fig. 2c), suggesting that overexpressed expression of MDR1 and Survivin play an significant role in acquired drug resistance
Summary
Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome. Chemoresistance can lead to chemotherapy failure and very poor prognosis; novel strategies are urgently required for patients with drug-resistant BL. Tabata et al BMC Complementary Medicine and Therapies (2020) 20:84 away from their target molecules via cytoplasmic vesicles or pump molecules. The upregulation of these molecules has leads to cause drug resistance by reducing intracellular anti-cancer drug accumulation [8,9,10,11,12], is regarded as a marker of poor prognosis [13,14,15,16,17,18]. Further studies are required on the underlying intracellular signaling pathways
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