Figure 3 - uploaded by Jan Škubník
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Tubulin binds a specific site between α and β subunit of a tubulin dimer, which causes inhibition of further microtubule polymerization. This phenomenon can be utilized in the treatment of gout and cancer.
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Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are no...
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Context 1
... aforementioned, microtubules play an essential role in cell division, because they form the mitotic spindle. By inhibition of its formation, it is possible to stop the cell division and consequently induce cell death, which can be utilized especially in cancer treatment (Figure 3). Nevertheless, the possible use of compound 1 in tumor chemotherapy is highly Compound 1 has exerted therapeutic effects in a range of various diseases. ...
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... aforementioned, microtubules play an essential role in cell division, because they form the mitotic spindle. By inhibition of its formation, it is possible to stop the cell division and consequently induce cell death, which can be utilized especially in cancer treatment (Figure 3). Nevertheless, the possible use of compound 1 in tumor chemotherapy is highly limited because of a very low selectivity of compound 1 for cancer cells, which results in a rather low therapeutic index [24]. ...
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... 2020, 25 , x FOR PEER REVIEW 6 of 41 limited because of a very low selectivity of compound 1 for cancer cells, which results in a rather low therapeutic index [24]. Figure 3. Tubulin binds a specific site between α and β subunit of a tubulin dimer, which causes inhibition of further microtubule polymerization. ...
Citations
... Paclitaxel (PTX), a mitotoxic agent (14), is extensively used in TNBC chemotherapy due to its cytotoxic effects (15). However, drug resistance often leads to treatment failure. ...
Chemoresistance is a major challenge in treating triple‑negative breast cancer (TNBC); chemotherapy remains the primary approach. The present study aimed to elucidate the role of guanylate‑binding protein 2 (GBP2) in activating autophagy in TNBC and its impact on the sensitivity of TNBC cells to paclitaxel (PTX). Transfection with lentivirus was performed to establish TNBC cell lines with stable, high GBP2 expression. The mRNA and protein levels of GBP2 expression were evaluated utilizing reverse transcription‑quantitative PCR and western blotting, respectively. Autophagy in TNBC cells was evaluated using immunoblotting, transmission electron microscopy and fluorescence microscopy. The PI3K/AKT/mTOR pathway proteins and their phosphorylation were detected by immunoblotting, and fluorescence co‑localization analysis was performed to evaluate the association between GBP2 and autophagy‑related protein 2 (ATG2). BALB/c NUDE mice were subcutaneously injected with GBP2 wild‑type/overexpressing MDA‑MB‑231 cells. Low GBP2 expression was detected in TNBC, which was associated with a poor prognosis. Overexpression of GBP2 suppressed cell growth, and especially enhanced autophagy in TNBC. Forced expression of GBP2 significantly increased the PTX sensitivity of TNBC cells, and the addition of autophagy inhibitors reversed this effect. GBP2 serves as a prognostic marker and exerts a notable inhibitory impact on TNBC. It functions as a critical regulator of activated autophagy by co‑acting with ATG2 and inhibiting the PI3K/AKT/mTOR pathway, which contributes to increasing sensitivity of TNBC cells to PTX. Therefore, GBP2 is a promising therapeutic target for enhancing TNBC treatment.
... However, due to their great clinical potential, they are of frequent choice for use in drug combinations, in which their side effects can be effectively eliminated. 34 The encapsulation of multiple agents with therapeutic potential into a single particle provides an opportunity for accurate and controlled delivery of multiple drugs to a target area that enhances the synergistic effect of both therapeutics. ...
Photodynamic therapy is an effective method for the treatment of several types of cancerous and noncancerous diseases. The key to the success of this treatment method is effective drug delivery to the site of action, for instance, a tumor. This ensures not only the high effectiveness of the therapy but also the suppression of side effects. But how to achieve effective targeted delivery? Lately, much attention has been paid to systems based on the so-called Trojan horse model, which is gaining increasing popularity. The principle of this model is that the effective drug is hidden in the internal structure of a nanoparticle, liposome, or nanoemulsion and is released only at the site of action. In this review article, we focus on drugs from the group of mitotic poisons, taxanes, and their use with photosensitizers in combined therapy. Here, we discuss the possibilities of how to improve the paclitaxel and docetaxel bioavailability, as well as their specific targeting for use in combined photo- and chemotherapy. Moreover, we also present the state of the art multifunctional drugs based on cabazitaxel which, owing to a suitable combination with photosensitizers, can be used besides photodynamic therapy and also in photoacoustic imaging or sonodynamic therapy.
... Among TIs, colchicine has unique properties. 7 Tubulin is a dynamic structural protein, and TIs are classified as stabilizers (sTI) or destabilizers (dTI). dTIs are associated with 5 binding sites named by an agent or agent class: colchicine, taxanes, laulimalide, epothilones, and vinca alkaloids. ...
... Even though paclitaxel (PTX; isolated from yew) has long been a well-known substance, it still attracts large attention in cancer research even nowadays [1]. The mechanism of action of this compound, belonging to the group of so-called mitotic poisons [2], is based on the stabilization of microtubule fibers. Upon microtubule stabilization, the function of the mitotic spindle is hampered, and deoxyribonucleic acid (DNA) segregation into daughter cells cannot occur properly, which results in cell cycle arrest followed by some type of programmed cell death, in most cases apoptosis. ...
Paclitaxel, a compound naturally occurring in yew, is a commonly used drug for the treatment of different types of cancer. Unfortunately, frequent cancer cell resistance significantly decreases its anticancer effectivity. The main reason for the resistance development is the paclitaxel-induced phenomenon of cytoprotective autophagy occurring by different mechanisms of action in dependence on a cell type and possibly even leading to metastases. Paclitaxel also induces autophagy in cancer stem cells, which greatly contributes to tumor resistance development. Paclitaxel anticancer effectivity can be predicted by the presence of several autophagy-related molecular markers, such as tumor necrosis factor superfamily member 13 in triple-negative breast cancer or cystine/glutamate transporter encoded by the SLC7A11 gene in ovarian cancer. Nevertheless, the undesired effects of paclitaxel-induced autophagy can be eliminated by paclitaxel co-administration with autophagy inhibitors, such as chloroquine. Interestingly, in certain cases, it is worthy of potentiating autophagy by paclitaxel combination with autophagy inducers, for instance, apatinib. A modern strategy in anticancer research is also to encapsulate chemotherapeutics into nanoparticle carriers or develop their novel derivatives with improved anticancer properties. Hence, in this review article, we summarize not only the current knowledge of paclitaxel-induced autophagy and its role in cancer resistance but mainly the possible drug combinations based on paclitaxel and their administration in nanoparticle-based formulations as well as paclitaxel analogs with autophagy-modulating properties.
... The wide clinical usage of classic MT drugs is hampered by notable drug resistance and toxicity, fueling the chase for novel compounds with improved characteristics (157), many of which are in clinical trials (158). Moreover, in recent years it has become evident that the requirement for anti-metastatic behavior should be evaluated as well as primary growth shrinkage (159)(160)(161)(162). ...
The ability of cells to switch between different invasive modes during metastasis, also known as invasion plasticity, is an important characteristic of tumor cells that makes them able to resist treatment targeted to a particular invasion mode. Due to the rapid changes in cell morphology during the transition between mesenchymal and amoeboid invasion, it is evident that this process requires remodeling of the cytoskeleton. Although the role of the actin cytoskeleton in cell invasion and plasticity is already quite well described, the contribution of microtubules is not yet fully clarified. It is not easy to infer whether destabilization of microtubules leads to higher invasiveness or the opposite since the complex microtubular network acts differently in diverse invasive modes. While mesenchymal migration typically requires microtubules at the leading edge of migrating cells to stabilize protrusions and form adhesive structures, amoeboid invasion is possible even in the absence of long, stable microtubules, albeit there are also cases of amoeboid cells where microtubules contribute to effective migration. Moreover, complex crosstalk of microtubules with other cytoskeletal networks participates in invasion regulation. Altogether, microtubules play an important role in tumor cell plasticity and can be therefore targeted to affect not only cell proliferation but also invasive properties of migrating cells.
... The primary issues with chemotherapy include cytotoxicity and drug resistance. VCR is an anticancer drug derived from the periwinkle plant that can affect mitosis by inhibiting tubulin binding and is used to treat various cancers (Skubnik et al., 2020;Skubnik et al., 2021). Although it has significant antitumor efficacy, it has been associated with high incidence of side effects due to its lack of cell selectivity. ...
Biological macromolecules have been widely used as biomedical carriers in treating non-small cell lung cancer (NSCLC) due to their biocompatibility, targeting, biodegradability, and antitumor efficacy. Nanotechnology has been used in clinics to treat many diseases, including cancer. Nanoparticles (NPs) can accumulate drugs into tumors because of their enhanced permeability and retention (EPR) effects. However, the lack of active targeting ligands affects NPs drug delivery. Arginine-glycine-aspartic (RGD), as a targeting ligand, has distinct advantages in targeting and safety. In the present study, an RGD peptide-modified nanogel called RGD−polyethylene glycol−poly (L-phenylalanine-co-L-cystine) (RGD−PEG−P (LP-co-LC−P (LP-co-LC) was investigated to deliver vincristine (VCR) as NSCLC therapy. The VCR-loaded targeted nanoparticle (RGD-NP/VCR) demonstrated excellent antitumor efficacy compared to the free drug (VCR) and untargeted nanoparticle (NP/VCR) without any significant side effects. RGD-NP/VCR has better tumor inhibition and fewer side effects, indicating its potential benefit in NSCLC treatment.
... The active search for new agents or new combinations of antitubulins with other agents being developed to reduce the toxic effect is in progress (Škubník et al., 2020). Several reviews have been published describing the principles and mechanisms of antitubulins' action (Dumontet and Jordan, 2010;Škubník et al., 2020) and the possibility of their use in the treatment of malignant diseases, when combining them with other agents. However, when developing new treatment approaches we should keep in mind that under certain conditions antitubulins can stimulate the activation of metastasis due to the transition to amoeboid movement. ...
Tumor shrinkage as a result of antitumor therapy is not the only and sufficient indicator of treatment success. Cancer progression leads to dissemination of tumor cells and formation of metastases - secondary tumor lesions in distant organs. Metastasis is associated with acquisition of mobile phenotype by tumor cells as a result of epithelial-to-mesenchymal transition and further cell migration based on cytoskeleton reorganization. The main mechanisms of individual cell migration are either mesenchymal, which depends on the activity of small GTPase Rac, actin polymerization, formation of adhesions with extracellular matrix and activity of proteolytic enzymes or amoeboid, which is based on the increase in intracellular pressure caused by the enhancement of actin cortex contractility regulated by Rho-ROCK-MLCKII pathway, and does not depend on the formation of adhesive structures with the matrix, nor on the activity of proteases. The ability of tumor cells to switch from one motility mode to another depending on cell context and environmental conditions, termed migratory plasticity, contributes to the efficiency of dissemination and often allows the cells to avoid the applied treatment. The search for new therapeutic targets among cytoskeletal proteins offers an opportunity to directly influence cell migration. For successful treatment it is important to assess the likelihood of migratory plasticity in a particular tumor. Therefore, the search for specific markers that can indicate a high probability of migratory plasticity is very important.
... CEP192 and phosphorylation of Aurora A are essential for mitotic progression and spindle assembly [32,34]. Thus, mitosis is a critical step in maintaining cell proliferation, and proper regulation of spindle and centrosome assembly during mitosis is important for cell survival following exposure to cytotoxic compounds [21,26,[35][36][37]. ...
... We found that exposure to 9,10-PQ inhibited mitotic entry and progression in HeLa cells. Since it is well-established that prolonged mitosis is associated with SAC activation due to insufficient spindle conditions [35][36][37], spindle assembly was impaired in 9,10-PQ-exposed cells. In fact, our data showed that exposure to 9,10-PQ disturbed bipolar spindle assembly and kMT attachment, resulting in mitotic delay and misaligned chromosomes in HeLa cells. ...
The polycyclic aromatic hydrocarbon quinone derivative 9,10-phenanthrenequinone (9,10-PQ) is one of the most abundant and toxic components found in diesel exhaust particles (DEPs). These DEPs are created during diesel fuel combustion and are considered the main source of urban air pollution. As 9,10-PQ can produce excessive reactive oxygen species (ROS) through redox cycling, it has been shown to exert potent cytotoxic effects against various cell types. However, the mechanisms underlying this cytotoxicity remain unclear. In this study, we showed that 9,10-PQ exerts cytotoxicity by impairing mitotic progression and spindle assembly in HeLa cells. Exposure to 9,10-PQ impaired spindle assembly and chromosome alignment, resulting in delayed mitotic entry and progression in HeLa cells. Furthermore, 9,10-PQ exposure decreased the CEP192 and p-Aurora A levels at the spindle poles. Notably, these mitotic defects induced by 9,10-PQ were not rescued by scavenging ROS, implying the ROS-independent activity of 9,10-PQ. Therefore, our results provide the first evidence that 9,10-PQ exerts its cytotoxicity through specific inhibition of mitotic progression and spindle assembly, independent of ROS.
... According to the US National Institute of Health (NIH) ispinesib was tested in 13 phase I/II clinical trials as monotherapy against several cancer diseases such as recurrent renal cell cancer, breast cancer, recurrent or metastatic head and neck cancer and liver and colorectal cancer. Although ispinesib showed a marginal safety profile but the efficacy of this compound as a single treatment is questionable and the best response was a partial response for ovarian and breast cancers [12,24]. ...
... Compound EMD534085 (Table 1, compound 8) showed KSP ATPase (IC 50 = 8 nM). The lipophilic core of this compound improved its stability and pharmacokinetic profile [24]. The first clinical, phase I study (3 + 3 design) considered EMD 534085 safety, pharmacokinetics and as antineoplastic agent against solid tumors or lymphoma. ...
Plain language summary
Scientists have recognized the importance of selective KSP inhibitors in the early 2000s and so various KSP protein inhibitors have been investigated. Only ten of these have been clinically evaluated for cancer treatment. Ispinesib (SB-715992) and filanesib (Arry-520) were the most promising small molecules in clinical trials against the KSP protein. Many challenges are faced during the development of an active anti-KSP drug; most importantly are the unsatisfactory clinical trial results. Designing dual inhibitors, antibody–drug conjugates, combination therapy and gene therapy approach are among the main strategies that are being investigated nowadays to find new effective KSP inhibitors. The scientific research efforts are still devoted to find an effective and tolerable KSP inhibitor drug that can gain US FDA approval.
... Vincristine and other vinca alkaloids belong to the group of mitotic poisons [4], particularly tubulin-binding compounds, which derive their biological properties from disrupting the function of microtubules. Microtubules are polymeric fibers composed of tubulin heterodimers. ...
Treatment of blood malignancies and other cancer diseases has been mostly unfeasible, so far. Therefore, novel treatment regimens should be developed and the currently used ones should be further elaborated. A stable component in various cancer treatment regimens consists of vincristine, an antimitotic compound of natural origin. Despite its strong anticancer activity, mostly, it cannot be administered as monotherapy due to its unspecific action and severe side effects. However, vincristine is suitable for combination therapy. Multidrug treatment regimens including vincristine are standardly applied in the therapy of non-Hodgkin lymphoma and other malignancies, in which it is combined with drugs of different mechanisms of action, mainly with DNA-interacting compounds (for example cyclophosphamide), or drugs interfering with DNA synthesis (for example methotrexate). Besides, co-administration of vincristine with monoclonal antibodies has also emerged, the typical example of which is the anti-CD20 antibody rituximab. Although in some combination anticancer therapies, vincristine has been replaced with other drugs exhibiting lesser side effects, though, in most cases, it is still irreplaceable. This is strongly evidenced by the number of active clinical trials evaluating vincristine in combination cancer therapy. Therefore, in this article, we have reviewed the most common cancer treatment regimens employing vincristine and bring an overview of current trends in the clinical development of this compound.
