Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line.

Laura Masuelli,Ilaria Tresoldi,Andrea Modesti,Rosanna Mattera,Enrica Di Stefano,Enrico De Smaele,Roberto Bei,Maria Gabriella Giganti,Monica Benvenuto,Giuseppina De Feudis,Massimo Fantini

doi:10.18632/oncotarget.14907

Abstract

Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients’ survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a “multifunctional drug”. We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species’intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR.

Highlights

Malignant mesothelioma (MM) is a primary tumor arising from the mesothelial cell linings of the serous membranes, most commonly involving the pleural and peritoneal spaces [1]
The survival of human (MM-B1, H-Meso-1, MMF1) and mouse (#40a) MM cells was evaluated by the Sulforhodamine B (SRB) assay after exposure to increasing doses of CUR (6.25-12.5-25-50 μM) or vehicle control (DMSO) for 24, 48 and 72 hours (Figure 1)
The inhibition of MM cells survival was paralleled by the increase of reactive oxygen species (ROS) intracellular production

Summary

Introduction

Malignant mesothelioma (MM) is a primary tumor arising from the mesothelial cell linings of the serous membranes, most commonly involving the pleural and peritoneal spaces [1]. Asbestos fibers can induce non-genotoxic damages, including the abnormal activation of the AP-1/TNF-α/NF-κB autocrine pathway, which increases cell survival after DNA damage and www.impactjournals.com/oncotarget promotes uncontrolled cell growth [6]. Targeted therapies improved the patients’ quality of the life and survival and the new generation of folate inhibitors alone or in combination with platinum derivatives, produced encouraging results, the absolute RRs continued to be limited compared to other tumors [16]. Polyphenols can be employed to inhibit the growth of cancer cells due to their ability to downregulate or block the activity of multiple targets involved in carcinogenesis [17,18,19,20,21]. It would be essential to further investigate the in vivo effect of CUR in a mouse model in which MM cells induce ascites in the peritoneal space

Methods

Results

Conclusion