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Pharmaceutics
Special Issues
Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders
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Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 5444

Special Issue Editors

Prof. Dr. Katarina Nikolic

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Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Interests: drug design; medicinal chemistry; epigenetic inhibitors; multitarget ligands
Prof. Dr. Biljana Bufan

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
Interests: animal models of autoimmune diseases; immunopharmacology; dendritic cells
Special Issues, Collections and Topics in MDPI journals
Dr. Dusan Ruzic

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Interests: medicinal chemistry; drug design; epigenetic inhibitors

Special Issue Information

Dear Colleagues,

Molecular mechanisms that underpin the onset and progression of malignant and neurodegenerative diseases seem to have little in common. Some epidemiological studies add weight to the inverse association between certain types of cancer and neurodegenerative diseases. However, there is no clear consensus on this connotation. Cancer cells escape cell death signals whereas aberrant activation of neuronal cell death is a common hallmark in neurodegenerative diseases. Numerous studies suggest common genetic and epigenetic factors that are implicated in cancer and neurodegeneration. Some of these include p53, ATM gene, Cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3 (GSK3), histone deacetylase 2 (HDAC2), Brain-derived Neurotrophic Factor (BDNF), changes in microRNA (miRNA) expression and many more.

To improve our understanding of the crosstalk between cancer and neurodegeneration, this Special Issue aims to discuss the novel therapeutic agents able to target aberrant molecular mechanisms common in cancer and neurodegenerative diseases.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Identification of prognostic markers for cancer and neurodegeneration
  • Identification of novel drug targets and signaling molecules
  • Repurposing of drug treatments for cancer and neurodegeneration
  • Drug design of novel compounds targeting cancer and neurodegeneration

We look forward to receiving your contributions.

Prof. Dr. Katarina Nikolic
Prof. Dr. Biljana Bufan
Dr. Dusan Ruzic
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design
  • cancer
  • neurodegeneration
  • repurposing
  • parkinson disease
  • multiple sclerosis
  • novel small-molecule inhibitors
  • kinases
  • epigenetics
  • aging

Published Papers (4 papers)

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Research

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19 pages, 4072 KiB  
Article
Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen
by Nikola Nedeljković, Miloš Nikolić, Petar Čanović, Milan Zarić, Radica Živković Zarić, Jelena Bošković, Marina Vesović, Jovana Bradić, Marijana Anđić, Aleksandar Kočović, Marina Nikolić, Vladimir Jakovljević, Zorica Vujić and Vladimir Dobričić
Pharmaceutics 2024, 16(1), 1; https://doi.org/10.3390/pharmaceutics16010001 - 19 Dec 2023
Cited by 3 | Viewed by 974
Abstract
The objective of this study was to synthesize seven novel thiourea derivatives of naproxen (8–14), examine the anti-inflammatory activity of the newly synthesized compounds, investigate the cytotoxic potential of both sets of synthesized compounds (1–7 and [...] Read more.
The objective of this study was to synthesize seven novel thiourea derivatives of naproxen (8–14), examine the anti-inflammatory activity of the newly synthesized compounds, investigate the cytotoxic potential of both sets of synthesized compounds (1–7 and 8–14), and select the most promising anti-inflammatory and antitumor drug candidates. The results of the in vivo anti-inflammatory study clearly showed that compounds 8 and 9 were capable of decreasing paw edema, as evident from a high percentage of inhibition (44.83% and 49.29%, respectively). In addition, the results of in vitro enzyme inhibition assays demonstrated that neither of the newly synthesized compounds reached 50% inhibition of 5-LOX at concentrations lower than 100 µM. In terms of antitumor potential, derivatives 3 and 8 exhibited strong cytotoxic effects on the HeLa cell line, suggesting the involvement of the extrinsic pathway of apoptosis. According to the overall results obtained for both sets of synthesized molecules, derivatives 4 and 8 can be underlined as molecules with the strongest anti-inflammatory activity, while derivatives 3 and 8 are the most promising cytotoxic agents. Full article
(This article belongs to the Special Issue Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders)
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14 pages, 4196 KiB  
Article
A Novel and Highly Selective Epidermal Growth Factor Receptor Inhibitor, SMUZ106, for the Treatment of Glioblastoma
by Ying Jiang, Chunhui Huang, Yaqi Huang, Lifan Long, Guowu Wu, Fengqiu Guo, Chuan Huang, Siming Liu, Zhengguang Zhu, Shaoyu Wu, Zhonghuang Li, Jiajie Zhang and Shanhe Wan
Pharmaceutics 2023, 15(5), 1501; https://doi.org/10.3390/pharmaceutics15051501 - 15 May 2023
Viewed by 1293
Abstract
Targeting the epidermal growth factor receptor (EGFR) is one of the potential ways to treat glioblastoma (GBM). In this study, we investigate the anti-GBM tumor effects of the EGFR inhibitor SMUZ106 in both in vitro and in vivo conditions. The effects of SMUZ106 [...] Read more.
Targeting the epidermal growth factor receptor (EGFR) is one of the potential ways to treat glioblastoma (GBM). In this study, we investigate the anti-GBM tumor effects of the EGFR inhibitor SMUZ106 in both in vitro and in vivo conditions. The effects of SMUZ106 on the growth and proliferation of GBM cells were explored through MTT and clone formation experiments. Additionally, flow cytometry experiments were conducted to study the effects of SMUZ106 on the cell cycle and apoptosis of GBM cells. The inhibitory activity and selectivity of SMUZ106 to the EGFR protein were proved by Western blotting, molecular docking, and kinase spectrum screening methods. We also conducted a pharmacokinetic analysis of SMUZ106 hydrochloride following i.v. or p.o. administration to mice and assessed the acute toxicity level of SMUZ106 hydrochloride following p.o. administration to mice. Subcutaneous and orthotopic xenograft models of U87MG-EGFRvIII cells were established to assess the antitumor activity of SMUZ106 hydrochloride in vivo. SMUZ106 could inhibit the growth and proliferation of GBM cells, especially for the U87MG-EGFRvIII cells with a mean IC50 value of 4.36 μM. Western blotting analyses showed that compound SMUZ106 inhibits the level of EGFR phosphorylation in GBM cells. It was also shown that SMUZ106 targets EGFR and presents high selectivity. In vivo, the absolute bioavailability of SMUZ106 hydrochloride was 51.97%, and its LD50 exceeded 5000 mg/kg. SMUZ106 hydrochloride significantly inhibited GBM growth in vivo. Furthermore, SMUZ106 inhibited the activity of U87MG-resistant cells induced by temozolomide (TMZ) (IC50: 7.86 μM). These results suggest that SMUZ106 hydrochloride has the potential to be used as a treatment method for GBM as an EGFR inhibitor. Full article
(This article belongs to the Special Issue Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders)
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Review

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33 pages, 1173 KiB  
Review
Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer
by Ana Vuletić, Katarina Mirjačić Martinović and Jelena Spasić
Pharmaceutics 2024, 16(1), 54; https://doi.org/10.3390/pharmaceutics16010054 - 29 Dec 2023
Viewed by 1268
Abstract
Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to [...] Read more.
Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy. Full article
(This article belongs to the Special Issue Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders)
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38 pages, 19757 KiB  
Review
Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer
by Milan Beljkas, Aleksandra Ilic, Alen Cebzan, Branko Radovic, Nemanja Djokovic, Dusan Ruzic, Katarina Nikolic and Slavica Oljacic
Pharmaceutics 2023, 15(11), 2581; https://doi.org/10.3390/pharmaceutics15112581 - 03 Nov 2023
Viewed by 1240
Abstract
Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated [...] Read more.
Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors. Full article
(This article belongs to the Special Issue Inhibitors in the Treatment of Cancer and Neurodegenerative Disorders)
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