Melanoma differentiation associated gene-7/interleukin-24 reverses multidrug resistance in human colorectal cancer cells

Paul B. Fisher,Zao-Zhong Su,David T. Curiel,Luni Emdad,Irina V. Lebedeva,Devanand Sarkar,Paul Dent

doi:10.1158/1535-7163.mct-07-0399

Abstract

Overexpression of the multidrug resistance 1 (MDR1) gene, encoding P-glycoprotein (P-gp), facilitates resistance to diverse chemotherapeutic drugs and current P-gp inhibitors display high toxicity. We studied the effects of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which exhibits cancer-specific apoptosis-inducing properties, in drug-sensitive (SW620) and drug-resistant (SW620/Dox) colorectal carcinoma cells. Adenovirus administered mda-7/IL-24, Ad.mda-7, effectively reversed resistance to doxorubicin-induced apoptosis in SW620/Dox cells by increased intracellular accumulation and decreased efflux of doxorubicin. Unexpectedly, P-gp-overexpressing cells (SW620/Dox) displayed increased apoptosis following Ad.mda-7 infection compared with parental SW620 cells, which correlated with more MDA-7/IL-24 protein in SW620/Dox than SW620 cell and potentially explains the increased sensitivity of P-gp-overexpressing cells to mda-7/IL-24. Transient overexpression of MDR1 in SW620 cells significantly increased apoptosis, decreased anchorage-independent growth, and increased MDA-7/IL-24 protein following Ad.mda-7 infection, whereas down-modulation of MDR1 in SW620/Dox cells by small interfering RNA decreased apoptosis following Ad.mda-7 infection. The increased mda-7/IL-24 sensitivity observed in SW620/Dox cells was partly due to increased reactive oxygen species generation and lower mitochondrial membrane potential. These findings confirm that mda-7/IL-24 is a potent MDR reversal agent, preferentially causing apoptosis in P-gp-overexpressing MDR cells, suggesting significant expanded clinical implications for the use of mda-7/IL-24 in treating neoplasms that have failed chemotherapy mediated by the P-gp MDR mechanism.

Highlights

Resistance to cytotoxic agents in tumor cells is one of the most serious obstacles to successful anticancer chemotherapy [1]
The effectiveness of chemotherapy, is seriously limited by multidrug resistance (MDR) that is mainly due to the overexpression of P-gp, a pump protein crucially involved in drug transport from the inside to the outside of cancer cells, preventing the intracellular accumulation of anticancer drugs inside cancer cells necessary for cytotoxic activity
The present study illustrates that treatment with mda-7/IL-24 can lead to a reversal of the MDR phenotype by inhibiting P-gp function, which allows for the intracellular accumulation of anticancer drugs

Summary

Introduction

Resistance to cytotoxic agents in tumor cells is one of the most serious obstacles to successful anticancer chemotherapy [1]. Cancer cells can become resistant to a single drug or to a family of drugs with identical mechanisms of action. They may acquire broad cross-resistance to mechanistically and structurally unrelated drugs, a phenomenon known as ‘‘classic’’ multidrug resistance (MDR). P-gp is capable of pumping several structurally unrelated chemotherapy drugs and other compounds out of the cell by using the energy of ATP hydrolysis (8 – 10), which results in decreased intracellular accumulation of compounds and resistance to drug cytotoxicity. Innate or acquired expression of P-gp, is a significant problem in cancer chemotherapy and successful inhibition of P-gp transporter function or its expression may overcome the MDR phenotype by increasing intracellular accumulation of anticancer drugs

Methods

Results

Conclusion