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New Drugs Regulating Cytoskeletons in Human Health and Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 11171

Special Issue Editors


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Guest Editor
Institute of Neurophysiopathology, CNRS UMR7051, Aix-Marseille University, Marseille, France
Interests: the role of the microtubule-associated protein Tau; the impact of new chemotherapeutic molecules

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Guest Editor
Mediterranean Institute of Biodiversity and Marine and Continental Ecology (IMBE), CNRS UMR7263, IRD237, Aix-Marseille University, Marseille, France
Interests: medicinal chemistry

E-Mail Website
Guest Editor
Institute of Neurophysiopathology, CNRS UMR7051, Aix-Marseille University, Marseille, France
Interests: cytoskeleton

Special Issue Information

Dear Colleagues,

It is a great pleasure to invite you to contribute to the Special Issue entitled “New drugs regulating cytoskeletons in human health and diseases”. The cytoskeletons constitute so many functional networks involved in biological processes, such as cell division and mechanotransduction, motility, intracellular organelles trafficking and macromolecules, and cell morphogenesis. Given that they are a key component of eukaryotic cells, it is not surprising that they continue to represent a prime pharmacological target in human health and diseases.

Exploratory research is being conducted in many laboratories around the world, and both synthetic and natural compounds or their derivatives with therapeutic properties are being investigated. Non-primary use of known drugs is also under research.

This Special Issue welcomes original articles and reviews addressing the search for new agents and the repurposing of known drugs for the treatment of cytoskeleton-associated diseases.

Dr. Gilles Breuzard
Dr. Maxime Robin
Dr. Hervé Kovacic
Guest Editors

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Keywords

  • tubulin
  • actine
  • cytoskeletons
  • associated proteins
  • pharmacological agent
  • repurposing of drugs
  • oncology
  • neurodegenerative diseases

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Published Papers (5 papers)

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Research

14 pages, 2809 KiB  
Communication
Therapeutic Contribution of Tau-Binding Thiazoloflavonoid Hybrid Derivatives Against Glioblastoma Using Pharmacological Approach in 3D Spheroids
by Emmanuelle T. Relave, Rayane Hedna, Attilio Di Maio, François Devred, Hervé Kovacic, Maxime Robin and Gilles Breuzard
Int. J. Mol. Sci. 2024, 25(21), 11785; https://doi.org/10.3390/ijms252111785 - 2 Nov 2024
Cited by 2 | Viewed by 1060
Abstract
Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure–activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid [...] Read more.
Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure–activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau-overexpressing GBM cells. Here, we evaluated the anticancer activities of the two lead compounds 2 and 9 using multi-cellular spheroids (MCSs) which represent an easy 3D human cell model to mimic GBM organization, physical constraints and drug penetration. The two compounds reduced cell evasion from spheroids up to three times, especially for Tau-expressing cells. As a first step towards a therapeutic approach, we quantified the effects of these compounds on MCS growth using two complementary protocols: single and repeated treatments. A single injection with compound 9 slowed down the growth of MCSs formed with U87 shCTRL cells by 40% at 10 µM. More interestingly, multiple treatment with compound 9 slowed the growth of U87 shCTRL spheroids by 40% at a concentration of 5 µM, supporting the increased bioavailability of compound 9 within MCSs. In conclusion, compound 9 deserves particular attention as promising candidate for specifically targeting Tau-expressing cancers such as GBM. Full article
(This article belongs to the Special Issue New Drugs Regulating Cytoskeletons in Human Health and Diseases)
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17 pages, 3127 KiB  
Article
Exploring the Role of Neuropeptide PACAP in Cytoskeletal Function Using Spectroscopic Methods
by Roland Gábor Vékony, Andrea Tamás, András Lukács, Zoltán Ujfalusi, Dénes Lőrinczy, Veronika Takács-Kollár and Péter Bukovics
Int. J. Mol. Sci. 2024, 25(15), 8063; https://doi.org/10.3390/ijms25158063 - 24 Jul 2024
Cited by 1 | Viewed by 1315
Abstract
The behavior and presence of actin-regulating proteins are characteristic of various clinical diseases. Changes in these proteins significantly impact the cytoskeletal and regenerative processes underlying pathological changes. Pituitary adenylate cyclase-activating polypeptide (PACAP), a cytoprotective neuropeptide abundant in the nervous system and endocrine organs, [...] Read more.
The behavior and presence of actin-regulating proteins are characteristic of various clinical diseases. Changes in these proteins significantly impact the cytoskeletal and regenerative processes underlying pathological changes. Pituitary adenylate cyclase-activating polypeptide (PACAP), a cytoprotective neuropeptide abundant in the nervous system and endocrine organs, plays a key role in neuron differentiation and migration by influencing actin. This study aims to elucidate the role of PACAP as an actin-regulating polypeptide, its effect on actin filament formation, and the underlying regulatory mechanisms. We examined PACAP27, PACAP38, and PACAP6-38, measuring their binding to actin monomers via fluorescence spectroscopy and steady-state anisotropy. Functional polymerization tests were used to track changes in fluorescent intensity over time. Unlike PACAP27, PACAP38 and PACAP6-38 significantly reduced the fluorescence emission of Alexa488-labeled actin monomers and increased their anisotropy, showing nearly identical dissociation equilibrium constants. PACAP27 showed weak binding to globular actin (G-actin), while PACAP38 and PACAP6-38 exhibited robust interactions. PACAP27 did not affect actin polymerization, but PACAP38 and PACAP6-38 accelerated actin incorporation kinetics. Fluorescence quenching experiments confirmed structural changes upon PACAP binding; however, all studied PACAP fragments exhibited the same effect. Our findings indicate that PACAP38 and PACAP6-38 strongly bind to G-actin and significantly influence actin polymerization. Further studies are needed to fully understand the biological significance of these interactions. Full article
(This article belongs to the Special Issue New Drugs Regulating Cytoskeletons in Human Health and Diseases)
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35 pages, 4005 KiB  
Article
Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-Based Hydroxamic Acids as Antimicrotubule Agents
by Elena Mariotto, Martina Canton, Chiara Marchioro, Andrea Brancale, Ernest Hamel, Katia Varani, Fabrizio Vincenzi, Tiziano De Ventura, Chiara Padroni, Giampietro Viola and Romeo Romagnoli
Int. J. Mol. Sci. 2024, 25(14), 7519; https://doi.org/10.3390/ijms25147519 - 9 Jul 2024
Cited by 2 | Viewed by 1666
Abstract
Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin–HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan [...] Read more.
Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin–HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6ai and 11ah, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6ag, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6. Full article
(This article belongs to the Special Issue New Drugs Regulating Cytoskeletons in Human Health and Diseases)
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19 pages, 3969 KiB  
Article
Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain
by Wen-Wen Li, Yan Zhao, Huai-Cun Liu, Jiao Liu, Sun-On Chan, Yi-Fei Zhong, Tang-Yu Zhang, Yu Liu, Wei Zhang, Yu-Qi Xia, Xiao-Chun Chi, Jian Xu, Yun Wang and Jun Wang
Int. J. Mol. Sci. 2024, 25(11), 5813; https://doi.org/10.3390/ijms25115813 - 27 May 2024
Cited by 5 | Viewed by 3649
Abstract
Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this [...] Read more.
Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol. Full article
(This article belongs to the Special Issue New Drugs Regulating Cytoskeletons in Human Health and Diseases)
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18 pages, 6907 KiB  
Article
Imbalance between Actin Isoforms Contributes to Tumour Progression in Taxol-Resistant Triple-Negative Breast Cancer Cells
by Vera Dugina, Maria Vasileva, Natalia Khromova, Svetlana Vinokurova, Galina Shagieva, Ekaterina Mikheeva, Aigul Galembikova, Pavel Dunaev, Dmitry Kudlay, Sergei Boichuk and Pavel Kopnin
Int. J. Mol. Sci. 2024, 25(8), 4530; https://doi.org/10.3390/ijms25084530 - 20 Apr 2024
Cited by 2 | Viewed by 2369
Abstract
The widespread occurrence of breast cancer and its propensity to develop drug resistance highlight the need for a comprehensive understanding of the molecular mechanisms involved. This study investigates the intricate pathways associated with secondary resistance to taxol in triple-negative breast cancer (TNBC) cells, [...] Read more.
The widespread occurrence of breast cancer and its propensity to develop drug resistance highlight the need for a comprehensive understanding of the molecular mechanisms involved. This study investigates the intricate pathways associated with secondary resistance to taxol in triple-negative breast cancer (TNBC) cells, with a particular focus on the changes observed in the cytoplasmic actin isoforms. By studying a taxol-resistant TNBC cell line, we revealed a shift between actin isoforms towards γ-actin predominance, accompanied by increased motility and invasive properties. This was associated with altered tubulin isotype expression and reorganisation of the microtubule system. In addition, we have shown that taxol-resistant TNBC cells underwent epithelial-to-mesenchymal transition (EMT), as evidenced by Twist1-mediated downregulation of E-cadherin expression and increased nuclear translocation of β-catenin. The RNA profiling analysis revealed that taxol-resistant cells exhibited significantly increased positive regulation of cell migration, hormone response, cell–substrate adhesion, and actin filament-based processes compared with naïve TNBC cells. Notably, taxol-resistant cells exhibited a reduced proliferation rate, which was associated with an increased invasiveness in vitro and in vivo, revealing a complex interplay between proliferative and metastatic potential. This study suggests that prolonged exposure to taxol and acquisition of taxol resistance may lead to pro-metastatic changes in the TNBC cell line. Full article
(This article belongs to the Special Issue New Drugs Regulating Cytoskeletons in Human Health and Diseases)
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