Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma

Our plain-English summary of Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma, by C. Zhang, Y. Hao, L. Wu, et al (International Journal of Oncology, 2018).

The study

• Authors: C. Zhang, Y. Hao, L. Wu, X. Dong, N. Jiang, B. Cong, J. Liu, W. Zhang, D. Tang, M. De Perrot, X. Zhao
• Journal: International Journal of Oncology
• Published: 2018;53(6):2531-2541
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin‑induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase‑independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

In plain English

This laboratory study tested curcumin, a turmeric ingredient, on RN5, a mouse malignant mesothelioma cell line, and in 20 male mice with RN5 tumors grown under the skin. It did not study asbestos exposure or human patients. In cell culture, the curcumin concentration needed for half its maximal effect (EC50) was 19.1±1.3 µM at 72 hours, against 7.09±1.14 µM for the chemotherapy drug cisplatin. The authors noted that cisplatin was more toxic to the cells. Curcumin raised the share of cells in the G2/M cell-cycle phase from under 10% in controls to 41% at 25 µM. It induced cell death without changing levels of activated caspase-3, -8 or -9 after 24 hours, and lowered PI3K, p-Akt, p-mTOR and p-p70S6K. On day 25, mean tumor volumes were 161 cubic millimetres with solvent alone, 120 with low-dose curcumin, 72 with high-dose curcumin and 58 with cisplatin. Curcumin-treated mice showed no obvious weight loss. High-dose tumors had significantly less CD31-stained area, a measure of blood vessel formation. The authors concluded that curcumin, possibly combined with platinum drugs, may be promising for treating malignant pleural mesothelioma.

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 study on a mouse mesothelioma cell line plus an animal experiment in tumor-bearing mice
• Who was studied: RN5 murine malignant mesothelioma cells. Also 20 male C57BL/6J mice, aged 6 weeks, injected under the skin with RN5 cells and randomly assigned to four groups of 4-5 mice. The work was done at The Second Hospital of Shandong University, China, and the cell line was provided by a laboratory in Toronto.
• Exposure: Curcumin. In cells it was tested at concentrations up to 50 µM, with 15, 20 and 25 µM used for mechanism tests. In mice it was given into the abdominal cavity at a low dose (200 mg/kg) or a high dose (500 mg/kg), five times every 5 days. Cisplatin was the comparison drug (30 µM in cells; 5 mg/kg in mice). Asbestos was not studied.
• Main results:
  • In RN5 cells at 72 hours, the EC50 of curcumin was 19.1±1.3 µM and the EC50 of cisplatin was 7.09±1.14 µM.
  • The authors judged cisplatin to be more toxic to RN5 cells than curcumin.
  • After 24 hours, under 10% of control (DMSO) cells were in the G2/M phase. In the 15, 20 and 25 µM curcumin groups the figures were 18%, 35% and 41%.
  • Curcumin did not change levels of activated caspase-3, -8 or -9 in RN5 cells after 24 hours.
  • Nuclear AIF in RN5 cells rose significantly with increasing curcumin dose after 24 hours.
  • In RN5 cells, increasing curcumin doses significantly lowered PI3K, p-Akt, p-mTOR and p-p70S6K.
  • In the mice on day 25, mean tumor volumes were 58 cubic millimetres with cisplatin, 72 with high-dose curcumin, 161 with solvent and 120 with low-dose curcumin.
  • Mice treated with curcumin showed no obvious body weight loss. Mice treated with cisplatin did lose weight, which the authors attributed to the drug's toxicity.
  • In tumors from the high-dose curcumin group, the CD31-positive area, used to assess blood vessel formation, was significantly lower.
• The authors' conclusion: The authors concluded that curcumin may have a promising application, and that curcumin combined with platinum-based drugs may be promising in treating malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors state that how curcumin inhibits blood vessel formation in malignant pleural mesothelioma remains unknown.

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, Angiogenesis, Malignant Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Translocation, Immunohistochemistry.

Related studies

• Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis — Y. Wang, A.K. Rishi, et al. (2011)
• Curcumin induces autophagy in ACC-MESO-1 cells — Y. Yamauchi, Y. Izumi, et al. (2012)
• Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells — L. Mayol, C. Serri, et al. (2015)
• Phosphatidylinositol Induces Caspase-Independent Apoptosis of Malignant Pleural Mesothelioma Cells by Accumulating AIF in the Nucleus — S. Kanemura, A. Tsuchiya, et al. (2015)
• Exploring inhibitory potential of Curcumin against various cancer targets by in silico virtual screening — A.B. Mahajanakatti, G. Murthy, et al. (2014)
• Curcumin: a double hit on malignant mesothelioma — J.M. Miller, J.K. Thompson, et al. (2014)

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