Progesterone Increases Apoptosis and Inversely Decreases Autophagy in Human Hepatoma HA22T/VGH Cells Treated with Epirubicin

Wai Hoong Chang ,Bau-Shan Hsieh,Kee-Lung Chang,Hsiao-Ling Cheng,King‐Teh Lee ,Chien‐Chih Chiu

doi:10.1155/2014/567148

Abstract

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. Epirubicin can induce intracellular reactive oxygen species and is widely used to treat unresectable HCC. Progesterone has been found to inhibit the proliferation of hepatoma cells. This study was designed to test the combined effects of epirubicin and progesterone on human hepatoma cell line, HA22T/VGH. These cells were treated with different concentrations of epirubicin with or without the coaddition of 30 μM progesterone and then analyzed for apoptosis, autophagy, and expressions of apoptotic-related proteins and multidrug-resistant gene. Epirubicin treatment dose-dependently inhibited the growth of HA22T/VGH cells. Addition of 30 μM progesterone, which was inactive alone, augmented the effect of epirubicin on the inhibition of growth of HA22T/VGH cells. Cotreatment with progesterone enhanced epirubicin-induced apoptosis, as evidenced by greater increase in caspase-3 activity and in the ratio of the apoptosis-regulating protein, Bax/Bcl-XL. The combination also caused a decrease in autophagy and in the expression of multidrug resistance-related protein 1 mRNA compared to epirubicin alone. This study shows the epirubicin/progesterone combination was more effective in increasing apoptosis and inversely decreasing autophagy on HA22T/VGH cells treated with epirubicin alone, suggesting that this combination can potentially be used to treat HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women, and it is the third most common cause of cancer-related deaths worldwide [1, 2]
The formation of acidic vesicular organelles (AVOs) but decreased the expression of light chain-3 (LC3)-I, whereas coaddition of progesterone decreased the formation of AVOs and reversed the expression of LC3-I. These results indicate that epirubicin may promote the turnover of LC3-I to LC3phospholipid conjugate (LC3-II), a possibility that is compatible with epirubicin-induced formation of AVOs during the same incubation period (24 h)
This study found that the addition of progesterone to epirubicin-treated HA22T/VGH cells significantly decreased the expression of multidrug resistance-related protein 1 (MRP-1) gene, a decrease that might be related to the reduction of autophagy

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women, and it is the third most common cause of cancer-related deaths worldwide [1, 2]. Local ablation therapy, and liver transplantation are the suggested curative therapies for HCC, while transarterial chemoembolization (TACE) has been used to treat unresectable HCC with some clinical efficacy [3,4,5]. Anthracyclines, such as doxorubicin or epirubicin, have been widely used to treat advanced HCC, to prevent or treat postoperative recurrence, and to downstage the disease before liver transplantation by systemic infusion or by transarterial route [6, 7].

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Results

Conclusion