Abstract
The 5-year survival rate of patients with B cell lymphoma is about 50% after initial diagnosis, mainly because of resistance to chemotherapy. Hence, it is necessary to understand the mechanism of chemo-resistance and to explore novel methods to circumvent multidrug resistance. Previously, we showed that an engineered cytotoxic fusion protein anti-CD19(Fab)-LDM (lidamycin), can induce apoptosis of B-lymphoma cells. Herein, we successfully established an adriamycin (ADR)-resistant B cell lymphoma cell line BJAB/ADR. The mRNA and protein level of ATP-binding cassette subfamily B member 1 (ABCB1) were significantly overexpressed in BJAB/ADR cells. Increased efflux function of ABCB1 was observed by analyzing intracellular accumulation and efflux of Rhodamine 123. The efflux of Rhodamine 123 could be significantly ameliorated by verapamil. Treatment with anti-CD19(Fab)-LDM at different concentrations induced cytotoxic response of BJAB/ADR cells similar to that of the sensitive cells. In vivo studies showed that anti-CD19(Fab)-LDM had better antitumor effect in BJAB and BJAB/ADR cell lymphoma xenografts compared with ADR or LDM treatment alone. Taken together, anti-CD19(Fab)-LDM can effectively inhibit the growth of BJAB/ADR cells both in vitro and in vivo. Anti-CD19(Fab)-LDM could be a promising molecule for the treatment of drug resistant cancers.
Highlights
Lymphomas are a common heterogeneic group of hematologic diseases, among which B cell origin lymphoma represents the largest proportion [1, 2]
The phospho-glycoprotein (P-gp, MDR1) mouse monoclonal antibody conjugated with Alexa Fluor 594, ABCG2 mouse monoclonal antibody conjugated with Alexa Fluor 488 and MRP1 mouse monoclonal antibody conjugated with Alexa Fluor 488 were obtained from Santa Cruz Biotechnology, Inc (Dallas, TX, USA)
The BJAB/ADR cell line was established after intermittent treatment with ADR at concentrations ranging from 37 to 294 nM in a stepwise increasing manner
Summary
Lymphomas are a common heterogeneic group of hematologic diseases, among which B cell origin lymphoma represents the largest proportion [1, 2]. Most patients who experience remission for more than 5 years have benefitted from the overall improvements in the treatment of B cell lymphomas. The clinical approaches to relapsed B lymphomas mainly involve in administering high-dose chemotherapeutic agents, using inhibitors to reverse drug resistance toward chemotherapy [4], or. To investigate the mechanisms involved in the acquisition of chemotherapy resistance and subsequent poor prognosis, it is necessary to establish a proper resistant cell model derived from a drug-sensitive human lymphoma cell line. Adriamycin (ADR; generic name: doxorubicin, DOX) is a chemotherapeutic drug frequently used in multiple clinical protocols of chemotherapy and is a critical drug in the treatment of lymphoma [12]. Establishing an ADR-resistant lymphoma cell model is useful for studying the mechanism of resistance in B cell lymphoma and for searching solutions regarding ADR resistance
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