Reversal Effect of Melanoma Differentiation Associated Gene‐7/Interleukin‐24 on Multidrug Resistance in Human Hepatocellular Carcinoma Cells

Abstract

Multidrug resistance is the main cause for failure of chemotherapy. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) has been implicated in the inhibition of human tumor cell proliferation. However, the reversing effect of mda-7/IL-24 on multidrug resistance of human hepatocellular carcinoma (HCC) is not fully clear. In this study, we investigated the effects of overexpression of the mda-7/IL-24 gene in human HCC. We established mda-7/IL-24 overexpressing BEL-7402/5-fluorouracil (5-FU) cell lines and their drug sensitivity to 5-FU and doxorubicin (DOX) which were investigated by MTT. Furthermore, we investigated the apoptotic rate and the intracellular accumulation of Rhodamine-123 and DOX by flow cytometry. We also studied the expression of multidrug resistance gene 1 (MDR1), lung resistance-related protein (LRP), and multidrug resistance-related protein 1 (MRP1) by real-time polymerase chain reaction and Western blotting. Transcriptional activation of AP-1 and NF-jB was determined by luciferase reporter assay. The drug sensitivity of 5-FU or DOX, the apoptotic rate, and the intracellular accumulation of Rhodamine-123 and DOX were increased, while the mRNA and protein expression levels of MDR1, LRP, and MRP1 were reduced. The transcriptional activation of AP-1 and NF-jB was suppressed in mda-7/IL-24 overexpressing BEL-7402/5-FU cells. Our results demonstrated that mda-7/IL-24 could restore the drug sensitivity through the downregulation of MDR1, MRP1, and LRP expression, as well as the transcriptional activation of AP-1 and NF-jB and effectively reverse MDR.

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

“…MTS assay results showed that Mda-7/IL-24 significantly retarded proliferation of Raji and Daudi cells, and enhanced the sensitivity of these lymphoma cells to various chemotherapy drugs, including CDDP, epirubicin and VCR, and that IC 50 was lower in cells transfected with Mda-7/IL-24 than in non-transfected and vector-transfected cells. These results were in good agreement with the effects of Mda-7/IL-24 on these types of tumor cells (2,5,6). In addition, although the apoptosis-inducing capability of Mda-7/IL-24 has been widely documented in various solid tumors, we did not observe significant induction of apoptosis in the two lymphoma cell lines.…”

“…Studies are required to elucidate the mechanisms of drug resistance, and new treatment strategies are needed to improve cure rates and survival in patients with lymphoma. Changes in molecular regulatory networks that increase anti-apoptotic activity and reduce the apoptosis of tumor cells are the primary mechanisms associated with resistance to chemotherapy drugs (2,17). Methods of enhancing sensitivity to chemotherapy and avoiding MDR remain among the most difficult problems in tumor treatment.…”

“…Although Mda-7/IL-24 has been widely regarded as an antitumor molecule and has been shown to inhibit hematopoietic tumor proliferation (5,6), little is known about its effects on lymphoma cell sensitivity to chemotherapy. Recent studies have shown that Mda-7/IL-24 could reverse MDR in human colorectal and hepatocellular cancers (2,19), but whether it plays a similar role in B cell lymphoma has not been determined. The present study is the first to show that transfection of endogenous Mda-7/IL-24 sensitized Raji and Daudi lymphoma cells to chemotherapy drugs by affecting factors related to chemotherapy drug resistance.…”

“…Based on their immunophenotypes, most lymphomas are B cell type (1). Although chemotherapy remains the treatment of choice for B cell lymphoma, the main barrier to its success is the development of multidrug resistance (MDR), by which tumors become insensitive to multiple chemotherapeutic agents after exposure to one (2). Tumor development of MDR is thought to be due to their overexpression of MDR-related genes.…”

Celecoxib enhances sensitivity to chemotherapy drugs of T‑cell lymphoma

“…At present, chemotherapy agents-based strategies remain the first choice for treatment of T-cell lymphoma, however poor prognosis is inevitable due to the occurrence of multidrug resistance (MDR) (2). The typical MDR phenotype is characterized by the overexpression of the MDR-associated proteins in the cytomembrane that serve as efflux pumps, to exclude the intracellular antitumor agents (3,4).…”