A novel antibody–drug conjugate anti-CD19(Fab)-LDM in the treatment of B-cell non-Hodgkin lymphoma xenografts with enhanced anticancer activity

Jiang, Linlin; Yang, Moon-Sik; Zhang, Xiaoyun; Bao, Shiqi; Ma, Li; Fan, Daiming; Zhou, Yuan; Xiong, Dongsheng; Zhen, Yong‐Su

doi:10.3109/1061186x.2015.1055568

Cited by 5 publications

(6 citation statements)

References 34 publications

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“…An increasing body of evidence suggests that aberrant microRNA expression enhances the development of drug resistance by interfering with the expression of target proteins that may be drug transporters, drug targets, or cell apoptosis- and cell-cycle-related components, resulting in cells with different degrees of sensitivity to chemotherapeutic drugs. Studies have showed that miRNAs such as miR-27a [ 3 ], miR-106a [ 4 ], miR-133a [ 5 ], miR-145 [ 6 ], miR-181b [ 7 ], miR-218 [ 8 ], and miR-326 [ 5 ] may be involved in the development of drug resistance by regulating relative gene expression. ABCB1 encodes a multi-drug-resistance gene ( MDR1 ), and is the most prominent member of the ABC transporter family, and it is the most thoroughly investigated member of this family [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1

et al. 2015

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BackgroundRecent studies have shown that microRNAs may regulate the ABCB1 gene (ATP-binding cassette, sub-family B [MDR/TAP], member 1). Computational programs have predicted that the 3’-untranslated region (3’-UTR) of ABCB1 contains a potential miRNA-binding site for miR-186. Here, we investigated the role of miR-186 in sensitizing ovarian cancer cells to paclitaxel and cisplatin.ResultsHuman ovarian carcinoma cell lines OVCAR3, A2780, A2780/DDP, and A2780/Taxol were exposed to paclitaxel or cisplatin with or without miR-186 transfection, and cell viability was determined by MTT assay. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were used to assess the MDR1, GST-π, and MRP1 expression levels. Dual-luciferase reporter assay was used to reveal the correlation between miR-186 and ABCB1. Lower miR-186 while higher MDR1 and GST-π mRNA expression levels were found in the A2780/Taxol and A2780/DDP cells than in the A2780 cells. After miR-186 transfection, all the cell lines showed increased sensitivity to paclitaxel and cisplatin. MiR-186 transfection induced apoptosis while anti-miR-186 transfection reduced apoptosis. The dual-luciferase reporter assay verified that that miR-186 combined with the 3’-untranslated region (UTR) of ABCB1. MDR1 and GST-π mRNA and protein expression levels were downregulated after transfection with miR-186 but upregulated following anti-miR-186 transfection compared to the mock and negative control cancer cells; however, the MRP1 expression levels did not significantly differ among the groups.ConclusionOur results are the first to demonstrate that miR-186 may sensitize ovarian cancer cell to paclitaxel and cisplatin by targeting ABCB1 and modulating the expression of GST-π.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-015-0207-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1

et al. 2015

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“…Previous experiments in our laboratory showed that the engineered fusion protein anti-CD19(Fab)-LDM exerted significant cytotoxic effects on BJAB cells (23). We performed the MTT assay to ascertain the cytotoxic effect of anti-CD19(Fab)-LDM toward BJAB/ADR cells.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that anti-CD19(Fab)-LDM suppresses tumor growth in a human B-cell lymphoma xenograft model (23). To assess whether the observed anti-CD19(Fab)-LDM-mediated inhibition of cell growth of MDR cells in vitro would extend to animal models, we established BJAB and BJAB/ADR xenograft tumor mouse models to investigate the MDR phenomenon in vivo to investigate the therapeutic effect of anti-CD19(Fab)-LDM on the BJAB/ADR xenograft model.…”

Section: Resultsmentioning

confidence: 99%

“…This type of biopharmaceutical drug is called antibody-drug conjugate (ADC) (48). Specifically, anti-C19(Fab)-LDM is an engineered fusion protein previously established in our laboratory and has been reported to have high antineoplastic activity toward B cell lymphoma (23). The fusion protein anti-CD19(Fab)-LDM was developed as a targeted therapy for lymphoma and induces significant tumor-specific cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…CD19 is a biomarker that is expressed on virtually all neoplastic cells of the B-cell lineage (21, 22). Previous studies demonstrated that the engineered fusion protein anti-CD19(Fab)-LDM, which comprises the chemo-drug lidamycin and anti-CD19(Fab) antibody, showed targeted cytotoxicity against lymphoma cells both in vitro and in vivo (23).…”

Section: Introductionmentioning

confidence: 99%

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An Engineered Fusion Protein Anti-CD19(Fab)-LDM Effectively Inhibits ADR-Resistant B Cell Lymphoma

et al. 2019

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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.

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Next Generation of Antibody-Drug Conjugates for Breast Cancer

Srivastava,

Osikoya,

Raman

2024

Interdisciplinary Cancer Research

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A novel antibody–drug conjugate anti-CD19(Fab)-LDM in the treatment of B-cell non-Hodgkin lymphoma xenografts with enhanced anticancer activity

Cited by 5 publications

References 34 publications

MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1

MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1

An Engineered Fusion Protein Anti-CD19(Fab)-LDM Effectively Inhibits ADR-Resistant B Cell Lymphoma

Next Generation of Antibody-Drug Conjugates for Breast Cancer

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