ADP sensitizes ZL55 cells to the activity of cisplatin

Our plain-English summary of ADP sensitizes ZL55 cells to the activity of cisplatin, by A. Muscella, L.G. Cossa, C. Vetrugno, et al (Journal of Cellular Physiology, 2019).

The study

• Authors: A. Muscella, L.G. Cossa, C. Vetrugno, G. Antonaci, S. Marsigliante
• Journal: Journal of Cellular Physiology
• Published: 2019;234(4):4409-4417
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor in which cisplatin therapy is commonly used, although its effectiveness is limited. It follows that research efforts dedicated to identify promising combinations that can synergistically kill cancer cells are needed. Because we recently demonstrated that ADP inhibits the proliferation of ZL55 cells, an MPM-derived cell line obtained from bioptic samples of asbestos-exposed patients. Our objective in this study was to investigate the hypothesis that ADP also potentiates the cytotoxic activity of cisplatin. Results show that in ZL55 cells ADP enhanced (a) the cytotoxicity of cisplatin by 12-fold, (b) the restraint of cell clonogenic potential cisplatin-mediated, and (c) the number of apoptotic cells. Cisplatin, but not ADP, caused caspases activation; nevertheless, poly(ADP-ribose) polymerase-1 was not only cleaved in cisplatin-treated cells but also in cells treated with ADP alone. Furthermore, ADP, but not cisplatin, decreased mTOR and 6SK phosphorylations. Both ADP and cisplatin increased p53 protein, but ADP was also able to enhance p53 messenger RNA. P53 silencing resulted in a very large decrement of cell death induced by ADP or by cisplatin and reverted ADP effects on mTOR/S6K phosphorylation, suggesting that activated p53 may act as a negative regulator of mTOR. Consistently, the inhibition of mTOR by rapamycin also sensitized cells to cisplatin, and the effects of cisplatin plus rapamycin were identical to those obtained with cisplatin plus ADP. These findings suggest that the combination of ADP and cisplatin may be a promising strategy for the clinical treatment of cisplatin-resistant MPM.

© 2018 Wiley Periodicals, Inc.

In plain English

This was a laboratory study of cells grown in dishes, not of patients. The authors used ZL55, a malignant pleural mesothelioma cell line that came from biopsy samples of asbestos-exposed patients. The study did not test asbestos. It tested the cancer drug cisplatin, alone and combined with ADP (adenosine diphosphate). Adding 50 µM ADP lowered the cisplatin concentration needed to halve cell numbers after 48 hours from 10.8 to 0.85 μM. The authors described this as a 12-fold increase in cisplatin's toxicity to these cells. The combination also reduced colony formation and increased apoptosis (programmed cell death). With cisplatin alone it took about 12 hours for half the cells to show apoptotic nuclei; with both agents the same changes appeared after 6 hours. ADP, but not cisplatin, reduced activation of a growth-signalling protein called mTOR. Silencing the p53 gene significantly reduced cell death from cisplatin and ADP. The mTOR blocker rapamycin sensitized cells to cisplatin just as ADP did. The authors concluded that combining ADP and cisplatin may be a promising strategy for treating cisplatin-resistant 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: In vitro laboratory experiment on a human mesothelioma cell line
• Who was studied: ZL55 cells, a human malignant pleural mesothelioma (epithelioid) cell line obtained from biopsy samples of asbestos-exposed patients; no patients were studied
• Exposure: Cisplatin at various concentrations, with and without 50 µM ADP; also rapamycin (10 µM) and nutlin-3α (8 μM) in some experiments. No asbestos fibers were tested in this study.
• Main results:
  • In ZL55 cells at 48 hr, 50 µM ADP lowered the IC50 of cisplatin from 10.8 ± 0.5 μM to 0.85 ± 0.6 μM, described as a 12-fold enhancement of cytotoxicity (p < 0.001, n = 5)
  • Adding ADP to cisplatin significantly increased cisplatin's cytotoxicity in the clonogenic (colony-forming) assay
  • With cisplatin alone it took about 12 hr to reach 50% apoptotic cells; with ADP plus cisplatin the same nuclear changes appeared after 6 hr
  • Cisplatin, but not ADP, activated caspases-3, -7 and -9
  • Cisplatin increased p53 protein but not p53 mRNA; ADP increased both
  • Silencing p53 with siRNA significantly reduced cell death induced by cisplatin and ADP
  • ADP, but not cisplatin, decreased mTOR phosphorylation without changing total mTOR
  • Blocking mTOR with rapamycin sensitized cells to cisplatin, with effects identical to cisplatin plus ADP
• The authors' conclusion: The authors concluded that combining ADP and cisplatin may be a promising strategy for the clinical treatment of cisplatin-resistant malignant pleural mesothelioma
• Limitations the authors state:
  • The authors noted that it remains to be determined whether such combinations will be selective for cancer cells, since toxicity would be a main problem

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: Cisplatin, Pleural Mesothelioma.

Related studies

• Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma — M.L. Hartman, J.M. Esposito, et al. (2010)
• Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells — Y.J. Lee, S.H. Lee (2017)
• Inhibition of ZL55 cell proliferation by ADP via PKC-dependent signalling pathway — A. Muscella, L.G. Cossa, et al. (2018)
• PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1 — G. Pinton, A.G. Manente, et al. (2013)
• Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed — Q. Li, K. Kawamura, et al. (2012)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)

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