In vitro and in vivo BNCT investigations using a carborane containing sulfonamide targeting CAIX epitopes on malignant pleural mesothelioma and breast cancer cells

Our plain-English summary of In vitro and in vivo BNCT investigations using a carborane containing sulfonamide targeting CAIX epitopes on malignant pleural mesothelioma and breast cancer cells, by D. Alberti, A. Michelotti, A. Lanfranco, et al (Scientific Reports, 2020).

The study

• Authors: D. Alberti, A. Michelotti, A. Lanfranco, N. Protti, S. Altieri, A. Deagostino, S. Geninatti Crich
• Journal: Scientific Reports
• Published: 2020;10(1):19274
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

This study aims at merging the therapeutic effects associated to the inhibition of Carbonic Anhydrase IX (CAIX), an essential enzyme overexpressed by cancer cells including mesothelioma and breast cancer, with those ones brought by the application of Boron Neutron Capture Therapy (BNCT). This task was pursued by designing a sulfonamido-functionalised-carborane (CA-SF) that acts simultaneously as CAIX inhibitor and boron delivery agent. The CAIX expression, measured by Western blot analysis, resulted high in both mesothelioma and breast tumours. This finding was exploited for the delivery of a therapeutic dose of boron (> 20 μg/g) to the cancer cells. The synergic cytotoxic effects operated by the enzymatic inhibition and neutron irradiation was evaluated in vitro on ZL34, AB22 and MCF7 cancer cells. Next, an in vivo model was prepared by subcutaneous injection of AB22 cells in Balb/c mice and CA-SF was administered as inclusion complex with a β-cyclodextrin oligomer. After irradiation with thermal neutrons tumour growth was evaluated for 25 days by MRI. The obtained results appear very promising as the tumour growth was definitively markedly lower in comparison to controls and the CAIX inhibitor alone. This approach appears promising and it call consideration for the design of new therapeutic routes to cure patients affected by this disease.

In plain English

This was a laboratory and mouse study of an experimental cancer treatment. It did not examine asbestos exposure. The authors made a boron-containing compound, CA-SF, designed both to block an enzyme called carbonic anhydrase IX (CAIX) and to carry boron into tumour cells for boron neutron capture therapy (BNCT), in which the tumour is then exposed to neutrons. CAIX levels were high in human breast cancer cells (MCF7), mouse mesothelioma cells (AB22) and human mesothelioma cells (ZL34). Cell survival fell as the CA-SF dose rose, while the approved drug acetazolamide had a negligible effect. After neutron irradiation, CA-SF-loaded AB22 and MCF7 cells showed reduced survival, but ZL34 cells did not differ from CA-SF alone. The authors then grew AB22 tumours under the skin of mice and compared groups of 5. CA-SF alone slowed tumour growth compared with untreated mice, and irradiation alone also reduced tumour volumes. With CA-SF plus irradiation, tumour growth stayed negligible through 25 days. The authors concluded that combining BNCT with targeted therapies may open new approaches to treating cancer patients.

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) cell experiments plus an animal experiment in mice with implanted tumours
• Who was studied: Three cancer cell lines: MCF7 human breast cancer, AB22 mouse mesothelioma and ZL34 human mesothelioma. Also adult male Balb/c mice with AB22 tumours injected under the skin of the neck: 6 mice in the boron distribution study, and groups of 5 in the treatment experiment (control, irradiated only, CA-SF only, and CA-SF plus irradiation). The work was done at the University of Torino and the University of Pavia, Italy. No dates are given.
• Exposure: Not an asbestos exposure study. The treatment studied was CA-SF, a sulfonamide-functionalised carborane, given to mice as three intravenous doses (37.5 mg/kg of boron each, on days 0, 2 and 6) in a complex with a beta-cyclodextrin oligomer. It was followed by 15 minutes of thermal neutron irradiation in the TRIGA Mark II reactor at the University of Pavia. In the cell experiments, CA-SF was compared with acetazolamide.
• Main results:
  • CAIX expression was high in both the mesothelioma and the breast cancer cells, and more intense in MCF7 and AB22 cells.
  • In all three cell lines, the percentage of viable cells decreased as the CA-SF concentration increased.
  • Acetazolamide had negligible inhibitory effect in the tested cell lines over the same concentration range.
  • CA-SF concentrations of 72, 187.5 and 130 µM loaded 60, 90 or 160 µg/g of boron into MCF7, ZL34 and AB22 cells respectively after 24 h. Cell vitality under these conditions was about 80% in all three lines.
  • In AB22 and MCF7 cells, survival of CA-SF-treated cells was significantly reduced after neutron irradiation.
  • In ZL34 cells, survival after CA-SF treatment alone was comparable to survival after CA-SF treatment plus irradiation.
  • Among cells that survived irradiation, only those pre-treated with CA-SF showed marked inhibition of proliferation.
  • In mice, the tumour-to-muscle boron ratio was 1:1 at 6 h and 1.7:1 at 16 h after CA-SF injection. Tumour boron was 13.8 ± 2.4 µg/g at 6 h and 7.4 ± 2.1 µg/g at 16 h.
  • In mice, CA-SF alone significantly inhibited tumour growth compared with control mice given the vehicle alone.
  • Mice irradiated without CA-SF also showed a significant decrease in tumour volumes compared with control and CA-SF-only mice.
  • In mice given CA-SF plus irradiation, tumour mass was dramatically reduced until 25 days after the first CA-SF dose. After 15 days, tumour growth remained negligible only in this group, while tumours began to regrow in the other groups.
• The authors' conclusion: The authors concluded that CA-SF hampered the growth of mesothelioma and breast cancer cells and had a synergic toxic effect with BNCT. In their view, the very limited tumour regrowth in treated and irradiated mice supports the idea that combining BNCT with targeted therapies may lead to new approaches to treating cancer patients.
• Limitations the authors state:
  • The authors suggested that the cyclodextrin carrier might prolong release of CA-SF, but stated that they did not investigate this.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma.

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