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.
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.
Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
Laura
L
Masuelli
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
Monica
M
Benvenuto
Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
Enrica
E
Di Stefano
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
Rosanna
R
Mattera
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
Massimo
M
Fantini
Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
Giuseppina
G
De Feudis
Department of Experimental Medicine, University of Rome "Sapienza", Rome, Italy.
Enrico
E
De Smaele
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
Ilaria
I
Tresoldi
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.
Maria Gabriella
MG
Giganti
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.|Center for Regenerative Medicine, (CIMER), University of Rome "Tor Vergata", Rome, Italy.
Andrea
A
Modesti
Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.|Center for Regenerative Medicine, (CIMER), University of Rome "Tor Vergata", Rome, Italy.
Roberto
R
Bei
D000818:Animals; D000969:Antinematodal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D023041:Xenograft Model Antitumor Assays
D000969:Antinematodal Agents; C505530:CASP8 protein, human; D053181:Caspase 8; D003474:Curcumin
apoptosis; autophagy; curcumin; malignant mesothelioma; proliferation