Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs

Abstract

Abstract. ) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC 50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC 50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells. Furthermore, the activities of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells were suppressed. These results indicated that Mda-7/IL-24 enhanced the sensitivity of B lymphoma cells to chemotherapy agents by altering the expression of multidrug-resistance genes via downregulating GTP-RhoA-ERK signaling pathway, suggesting that treatment of B cell lymphomas with Mda-7/IL-24 could avoid MDR.

The clinical significance of Mda‑7/IL‑24 and C‑myb expression in tumor tissues of patients with diffuse large B cell lymphoma

“…The quality of RNA was assessed by EB staining analysis after agarose gel electrophoresis. RT-qPCR assay was used to analyze the expression levels of Mda-7/IL-24 and C-myb mRNA in DLBCL and normal lymph node tissues, according to our previous protocol ( 2 ). The qPCR cycling conditions were as follows: 95°C for 10 min, followed by 40 cycles of 95°C for 15 sec, 60°C for 15 sec and 60°C for 1 min.…”

“…Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of hematopoietic malignancy originating from lymphoid system, accounting for ~40% of non-Hodgkin's lymphoma worldwide ( 1 ). Although the chemotherapy of DLBCL has been obviously improved in the past 20 years, the overall survival of a large number of DLBCL patients remains unsatisfactory, especially when they are diagnosed with bone marrow metastasis ( 2 ). Recurrence, multidrugs-resistance and metastasizing to bone marrow have become the biggest barriers for improving survival in clinical situations ( 3 ).…”

Low expression of Mda-7/IL-24 and high expression of C-myb in tumour tissues are predictors of poor prognosis for Burkitt lymphoma patients

“…To investigate the effects of overexpressing Mda-7/IL-24 on expression of C-myb in Burkitt lymphoma cells, Raji and Daudi cells were stably transfected with the lentiviral vector encoding the human Mda-7/IL-24 gene using LipofectamineTM2000 and the pPACKH1TM Lentivector Packaging kit (pPACKH1-REV, pPACKH1-GAG and pVSV-G) as previously described [2].…”

“…Burkitt lymphoma is one of the most common subtypes of paediatric haematopoietic malignancy and accounts for approximately 40% of newly diagnosed non-Hodgkin's lymphoma in children and adolescents [1]. Although high-dose combination chemotherapy is an effective strategy for the treatment of Burkitt lymphoma, a poor prognosis is inevitable for the patients due to recurrence, invasion of bone marrow tissue and development of chemotherapy resistance [2,3]. However, the exact mechanisms involved in occurrence and progression of Burkitt lymphoma remain unclear.…”

Mda-7/IL-24 induces the differentiation of B cell lymphoma via activation of the P38 mitogen activated protein kinase signaling pathway

“…B cell lymphoma is a clinical hematopoietic malignancy originating from the lymphoid system and is the most common subtype of non-Hodgkin's lymphoma, with high mortality worldwide (1). The prevalence of B cell lymphoma and its poor prognosis following chemotherapy indicates requirement to identify alternativestrategies for its treatment (2). A novel approach for tumor treatment is to use agents that inhibit growth of tumor cells by inducing terminal differentiation, a strategytermed 'differentiation therapy' (3).…”