Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: a new strategy for anticancer therapy

Our plain-English summary of Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: a new strategy for anticancer therapy, by R. Delatouche, I. Denis, M. Grinda, et al (European Journal of Pharmaceutics and Biopharmaceutics, 2013).

The study

• Authors: R. Delatouche, I. Denis, M. Grinda, F. El Bahhaj, E. Baucher, F. Collette, V. Héroguez, M. Grégoire, C. Blanquart, P. Bertrand
• Journal: European Journal of Pharmaceutics and Biopharmaceutics
• Published: 2013;85(3 Pt B):862-72
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The aim of this study was to develop clickable prodrugs bearing a tunable pH responsive linker designed for acidic pH-mediated release of histone deacetylase inhibitors. HDACi are an important class of molecules belonging to the epigenetic modulators used for innovative cancer strategies. The behavior of these prodrugs was determined by a bioluminescence resonance energy transfer assay in living tumor cells. This work demonstrated that this innovative type of clickable prodrugs entered cancer cells and showed restored anti proliferative properties attributed to the effective release of the HDAC inhibitors. A correlation between kinetic studies, dose responses, and biological activities was obtained, making such clickable prodrugs good candidates for new strategies in epigenetic-oriented anticancer therapies.

Copyright © 2013 Elsevier B.V. All rights reserved.

In plain English

This laboratory study did not examine asbestos exposure. The authors made 'prodrug' versions of two cancer drugs called histone deacetylase inhibitors, SAHA (vorinostat) and CI-994. A prodrug is an inactive form designed to release the active drug, here in acidic conditions. They made three versions of each (4a to 4c for SAHA, 5a to 5c for CI-994). They measured how fast each broke down in buffer solutions of different acidity. They then tested the compounds in laboratory cells, including cell lines from patients with malignant pleural mesothelioma or lung adenocarcinoma. Version 4b had a half-life of 20 hours at pH 4.3. In a cell test of histone acetylation, a sign of the drug blocking its target, 4b and 4c worked at concentrations similar to free SAHA; 4a needed far more. In cancer cell survival tests, the free drugs and all prodrugs except 4a reduced survival; free SAHA worked at the lowest doses, 4b and 4c at higher ones. The authors concluded that versions other than series c gave prolonged release, and that benefits in living animals still had to be tested in mice.

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: chemical synthesis of prodrugs, measurement of breakdown rates in buffer solutions, and experiments on cell lines grown in the laboratory (no human or animal subjects)
• Who was studied: Cell lines: a pleural mesothelial cell line (MeT-5A) obtained from ATCC; two mesothelioma cell lines (Meso13, Meso34) and two lung adenocarcinoma cell lines (ADCA 153, ADCA 72) established from pleural fluids of patients
• Exposure: No asbestos exposure was studied. Cells were treated with the drugs SAHA and CI-994, three prodrug versions of each (4a to 4c and 5a to 5c), and the alcohols (compounds 3) left behind after the drug is released
• Main results:
  • In buffer solutions, SAHA prodrug 4b had a half-life of 20 hours at pH 4.3 and 4 days at pH 7.3
  • CI-994 prodrug 5a had a half-life of 30 minutes at pH 4.3. The text gives 4 days at pH 7.3; Table 1 lists 3.6 days
  • SAHA prodrug 4a was stable at every pH tested; versions 4c and 5c broke down rapidly
  • In the cell-based test of histone H3 acetylation (BRET), the concentrations giving half the maximum effect were 0.42 plus or minus 0.08 micromolar for SAHA, 0.59 plus or minus 0.18 for 4b and 0.75 plus or minus 0.07 for 4c. The authors interpreted this as effective release of the drug from 4b and 4c. Prodrug 4a needed 7.17 plus or minus 3.19 micromolar
  • For CI-994 and prodrugs 5a, 5b and 5c, these BRET concentrations were 0.86, 6.20, 0.68 and 8.88 micromolar respectively. The authors said this did not clearly match the breakdown rates measured in buffer
  • Over time, free SAHA produced the largest maximum BRET signal (93.9 mBu), compared with 4c (66.2), 4b (44.3) and 4a (15.8)
  • For the CI-994 prodrugs, differences between the three versions were not significant. Version 5a needed 48 hours to reach its maximum signal
  • In the mesothelioma and lung adenocarcinoma cells treated for 72 hours, the free drugs and all prodrugs except 4a were toxic, depending on concentration. The released alcohols 3 were tested separately and were not toxic (see below)
  • Free SAHA reduced cell survival at the lowest doses: half-inhibitory concentrations were 1.47 plus or minus 0.65 micromolar in the mesothelioma lines and 1.71 plus or minus 0.94 micromolar in the adenocarcinoma lines
  • Prodrugs 4c and 4b gave intermediate half-inhibitory concentrations in the survival tests. Table 3 lists 4b at 9.39 (mesothelioma) and 17.32 (adenocarcinoma) micromolar, and 4c at 4.11 and 5.22 micromolar. Prodrug 4a did not affect cell survival
  • The alcohols left after drug release (compounds 3) were not toxic at the tested concentrations. The authors took this as confirming that the effects came from the released drugs
• The authors' conclusion: The authors concluded that, except for series c, the prodrugs gave prolonged release over time in buffer solutions. They correlated this with slower restoration of drug activity in cells. They stated that the expected reduction in side effects would need to be checked in mouse models of tumors
• Limitations the authors state:
  • Whether the compounds collected in the acidic compartments inside cells could not be determined, because the molecules have no detectable label
  • For the fastest-breaking compounds, half-lives could not be measured accurately
  • The prodrugs could not be given by mouth, because stomach acid would release the drug
  • The proposed benefits were not tested in animals; mouse studies are still needed

Topics

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

Related studies

• Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials — P.K. Paik, L.M. Krug (2010)
• The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy — P. Bertrand, C. Blanquart, et al. (2019)
• Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma — D. Bensaid, T. Blondy, et al. (2018)
• Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts — S.E. Pratt, S. Durland-Busbice, et al. (2013)
• Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation — S. Kalari, N. Moolky, et al. (2012)
• Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells — K. Pillai, A. Ehteda, et al. (2014)

Browse return to medical research.