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Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma

Simón Serrano, Sonia LU ; Tavecchio, Michele LU ; Grönberg, Alvar ; Sime, Wondossen LU ; Jemaà, Mohamed LU ; Moss, Steven ; Gregory, Matthew Alan ; Gallay, Philippe ; Elmér, Eskil LU orcid and Hansson, Magnus Joakim LU orcid , et al. (2021) In Cancers 13(12).
Abstract

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient's life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel... (More)

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient's life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G2/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancers
volume
13
issue
12
article number
3041
publisher
MDPI AG
external identifiers
  • pmid:34207224
  • scopus:85108117236
ISSN
2072-6694
DOI
10.3390/cancers13123041
language
English
LU publication?
yes
id
e829f7e2-6d91-4616-8959-f0ea779edb33
date added to LUP
2021-07-05 10:01:34
date last changed
2024-02-20 09:10:41
@article{e829f7e2-6d91-4616-8959-f0ea779edb33,
  abstract     = {{<p>Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient's life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G2/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.</p>}},
  author       = {{Simón Serrano, Sonia and Tavecchio, Michele and Grönberg, Alvar and Sime, Wondossen and Jemaà, Mohamed and Moss, Steven and Gregory, Matthew Alan and Gallay, Philippe and Elmér, Eskil and Hansson, Magnus Joakim and Massoumi, Ramin}},
  issn         = {{2072-6694}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma}},
  url          = {{http://dx.doi.org/10.3390/cancers13123041}},
  doi          = {{10.3390/cancers13123041}},
  volume       = {{13}},
  year         = {{2021}},
}