Oncotarget

Research Papers:

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

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Oncotarget. 2017; 8:34405-34422. https://doi.org/10.18632/oncotarget.14907

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Abstract

Laura Masuelli1, Monica Benvenuto2, Enrica Di Stefano1, Rosanna Mattera2, Massimo Fantini2, Giuseppina De Feudis1, Enrico De Smaele1, Ilaria Tresoldi2, Maria Gabriella Giganti2, Andrea Modesti2,3 and Roberto Bei2,3

1Department of Experimental Medicine, University of Rome “Sapienza”, Rome, Italy

2Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Rome, Italy

3Center for Regenerative Medicine, (CIMER), University of Rome “Tor Vergata”, Rome, Italy

Correspondence to:

Roberto Bei, email: bei@med.uniroma2.it

Keywords: curcumin, malignant mesothelioma, apoptosis, autophagy, proliferation

Received: November 04, 2016    Accepted: December 13, 2016    Published: January 30, 2017

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.


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