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

Our plain-English summary of 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, by L. Masuelli, M. Benvenuto, E. Di Stefano, et al (Oncotarget, 2017).

The study

• Authors: L. Masuelli, M. Benvenuto, E. Di Stefano, R. Mattera, M. Fantini, G. De Feudis, E. De Smaele, I. Tresoldi, M.G. Giganti, A. Modesti, R. Bei
• Journal: Oncotarget
• Published: 2017;8(21):34405-34422
• Cited by: 70 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory and animal study tested curcumin, a compound from the plant Curcuma longa, on malignant mesothelioma cells. No people were studied, and asbestos exposure was not tested. The authors treated three human mesothelioma cell lines (MM-B1, H-Meso-1, MM-F1) and one mouse line (#40a) with curcumin at 6.25 to 50 µM. Curcumin reduced cell survival more at higher doses and longer times. The dose that halved survival after 72 hours ranged from 18.38 µM (H-Meso-1) to 40.92 µM (#40a). After 24 hours at 25 µM, 29% to 53% of treated cells showed a marker of programmed cell death (apoptosis). A caspase blocker reduced or abolished this effect. Curcumin also raised reactive oxygen levels and started the cell's recycling process (autophagy), which then stalled. Mice were injected in the abdomen with #40a cells, 6 mice per group. Those given weekly curcumin into the abdomen had a median survival of 5 weeks, compared with 3 weeks for mice given corn oil alone (p=0.0009). The authors concluded that their findings may have implications for designing mesothelioma treatment using curcumin.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cell lines plus an animal experiment in mice
• Who was studied: Three human malignant mesothelioma cell lines: H-Meso-1 (epithelial), MM-B1 (biphasic) and MM-F1 (sarcomatous). One mouse mesothelioma cell line (#40a, derived from the 40 cell line). Groups of 6 C57BL/6 mice, aged 6 to 8 weeks, injected in the peritoneal cavity with #40a cells, University of Rome Tor Vergata.
• Exposure: Curcumin at 6.25 to 50 µM in cell culture, compared with the solvent DMSO. In mice, 1.5 mg curcumin in corn oil was injected into the peritoneal cavity once a week, compared with corn oil alone. No asbestos exposure was studied.
• Main results:
  • Doses of curcumin that halved cell survival at 48 and 72 hours: 28.85 and 25.73 µM for MM-B1; 22.21 and 18.38 µM for H-Meso-1; 29.45 and 30.47 µM for MM-F1; 33.13 and 40.92 µM for #40a.
  • Curcumin increased reactive oxygen species production in a dose-dependent way in all the mesothelioma cell lines, compared with the solvent.
  • The authors interpreted the results as showing that curcumin triggered autophagy but that the process was then blocked, as shown by an increase in the protein p62.
  • Percentage of cells that were apoptotic (activated caspase 3) after 25 µM curcumin for 24 hours: 46% for MM-F1, 29% for MM-B1, 53% for H-Meso-1 and 34% for #40a (each p less than 0.001).
  • The caspase inhibitor Z-VAD-FMK significantly reduced curcumin-induced apoptosis in the MM-F1 and #40a cells and abolished it in the MM-B1 and H-Meso-1 cells.
  • Curcumin caused the protein NF-κB to accumulate in the cytoplasm of all the cell lines, rather than in the nucleus.
  • In the mice, after 3 weeks of treatment, the mean abdominal circumference was 9.3 cm in curcumin-treated mice compared with 12.5 cm in control mice (p=0.0008).
  • Median survival was 5 weeks for curcumin-treated mice and 3 weeks for corn oil-treated mice (p=0.0009). One curcumin-treated mouse was still alive at ten weeks.
  • The authors reported that the risk of developing tumors in corn oil-treated mice was 39.12 relative to curcumin-treated mice. Table 4 gives this as a hazard ratio of 39.12, with a 95% confidence interval of 4.481 to 341.6.
• The authors' conclusion: The authors concluded that their findings may have implications for the design of mesothelioma treatment using curcumin in addition to other drugs.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Ascites, Reactive Oxygen Species (ROS), Translocation, Median Overall Survival.

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• Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells — K.E. Hwang, Y.S. Kim, et al. (2015)

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