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Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.
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Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs' effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.
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Aminoácidos , Xantonas , Humanos , Xantonas/farmacología , Xantonas/química , Línea Celular Tumoral , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genéticaRESUMEN
Recently, the diarylpentanoid BP-M345 (5) has been identified as a potent in vitro growth inhibitor of cancer cells, with a GI50 value between 0.17 and 0.45 µM, showing low toxicity in non-tumor cells. BP-M345 (5) promotes mitotic arrest by interfering with mitotic spindle assembly, leading to apoptotic cell death. Following on from our previous work, we designed and synthesized a library of BP-M345 (5) analogs and evaluated the cell growth inhibitory activity of three human cancer cell lines within this library in order to perform structure-activity relationship (SAR) studies and to obtain compounds with improved antimitotic effects. Four compounds (7, 9, 13, and 16) were active, and the growth inhibition effects of compounds 7, 13, and 16 were associated with a pronounced arrest in mitosis. These compounds exhibited a similar or even higher mitotic index than BP-M345 (5), with compound 13 displaying the highest antimitotic activity, associated with the interference with mitotic spindle dynamics, inducing spindle collapse and, consequently, prolonged mitotic arrest, culminating in massive cancer cell death by apoptosis.
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Antimitóticos , Antineoplásicos , Neoplasias , Humanos , Antimitóticos/farmacología , Mitosis , Proliferación Celular , Ciclo Celular , Huso Acromático/metabolismo , Neoplasias/metabolismo , Apoptosis , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/metabolismoRESUMEN
The "Warburg effect" consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.
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Virtual reality (VR) allows visuotactile interaction in a virtual environment. VR has several potential applications such as surgical training, phobia treatments, and gait rehabilitation. However, further interface development is required. Therefore, the objective of this study was to develop a noninvasive wearable device control to a VR gait training program. It consists of custom-made insoles with vibratory actuators, and plantar pressure sensor-based wireless interface with a VR game. System usability testing involved a habituation period and three gaming sessions. Significant gait improvement was associated with game scores (P < 0.05). This VR gait training system allowed real-time virtual immersive interaction with anticipatory stimulus and feedback during gait.
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Marcha , Realidad Virtual , Humanos , Interfaz Usuario-Computador , Terapia por EjercicioRESUMEN
In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on the combination of subunits of two promising antiproliferative compounds (CM-M345 (1) and BP-M345 (2)), previously obtained by our research group, are reported. In order to expand the structure-activity relationship (SAR) knowledge, a new series of 7-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (6, 7, and 13) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI50 = 2.66-3.26 µM), showing hybrid 7 selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53-MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound 7 emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death.
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Oral cancer is a highly aggressive tumor with invasive properties that can lead to metastasis and high mortality rates. Conventional treatment strategies, such as surgery, chemotherapy, and radiation therapy, alone or in combination, are associated with significant side effects. Currently, combination therapy has become the standard practice for the treatment of locally advanced oral cancer, emerging as an effective approach in improving outcomes. In this review, we present an in-depth analysis of the current advancements in combination therapies for oral cancer. The review explores the current therapeutic options and highlights the limitations of monotherapy approaches. It then focuses on combinatorial approaches that target microtubules, as well as various signaling pathway components implicated in oral cancer progression, namely, DNA repair players, the epidermal growth factor receptor, cyclin-dependent kinases, epigenetic readers, and immune checkpoint proteins. The review discusses the rationale behind combining different agents and examines the preclinical and clinical evidence supporting the effectiveness of these combinations, emphasizing their ability to enhance treatment response and overcome drug resistance. Challenges and limitations associated with combination therapy are discussed, including potential toxicity and the need for personalized treatment approaches. A future perspective is also provided to highlight the existing challenges and possible resolutions toward the clinical translation of current oral cancer therapies.
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The viability of SARS-CoV-2 on food surfaces and its propagation through the food chain has been discussed by several stakeholders, as it may represent a serious public health problem, bringing new challenges to the food system. This work shows for the first time that edible films can be used against SARS-CoV-2. Sodium alginate-based films containing gallic acid, geraniol, and green tea extract were evaluated in terms of their antiviral activity against SARS-CoV-2. The results showed that all these films have strong in vitro antiviral activity against this virus. However, a higher concentration of the active compound (1.25%) is needed for the film containing gallic acid to achieve similar results to those obtained for lower concentrations of geraniol and green tea extract (0.313%). Furthermore, critical concentrations of the active compounds in the films were used to evaluate their stability during storage. Results showed that gallic acid-loaded films lose their activity from the second week of storage, while films with geraniol and green tea extract only show a drop in activity after four weeks. These results highlight the possibility of using edible films and coatings as antiviral materials on food surfaces or food contact materials, which may help to reduce the spreading of viruses through the food chain.
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COVID-19 , Películas Comestibles , Humanos , Alginatos , Embalaje de Alimentos/métodos , SARS-CoV-2 , Antioxidantes , Extractos Vegetales/farmacología , Té , Antivirales/farmacología , Ácido Gálico/farmacologíaRESUMEN
Subclinical acute kidney injury (subAKI) is characterized by tubule-interstitial injury without significant changes in glomerular function. SubAKI is associated with the pathogenesis and progression of acute and chronic kidney diseases. Currently, therapeutic strategies to treat subAKI are limited. The use of gold nanoparticles (AuNPs) has shown promising benefits in different models of diseases. However, their possible effects on subAKI are still unknown. Here, we investigated the effects of AuNPs on a mouse model of subAKI. Animals with subAKI showed increased functional and histopathologic markers of tubular injury. There were no changes in glomerular function and structure. The animals with subAKI also presented an inflammatory profile demonstrated by activation of Th1 and Th17 cells in the renal cortex. This phenotype was associated with decreased megalin-mediated albumin endocytosis and expression of proximal tubular megalin. AuNP treatment prevented tubule-interstitial injury induced by subAKI. This effect was associated with a shift to an anti-inflammatory Th2 response. Furthermore, AuNP treatment preserved megalin-mediated albumin endocytosis in vivo and in vitro. AuNPs were not nephrotoxic in healthy mice. These results suggest that AuNPs have a protective effect in the tubule-interstitial injury observed in subAKI, highlighting a promising strategy as a future antiproteinuric treatment.
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Lesión Renal Aguda , Nanopartículas del Metal , Ratones , Animales , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Oro/farmacología , Túbulos Renales Proximales , Modelos Animales de Enfermedad , Proteinuria/metabolismo , Proteinuria/patología , Albúminas/metabolismo , Lesión Renal Aguda/metabolismoRESUMEN
Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, causing SAC-induced mitotic arrest, or mitotic drivers, pushing cells through aberrant mitosis by overriding SAC. These drugs, although advancing to clinical trials, exhibit unsatisfactory cancer treatment outcomes as monotherapy, probably due to variable cell fate responses driven by cyclin B degradation and apoptosis signal accumulation networks. We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver). Our aim was to steer treated cancer cells towards cell death. BH3-mimetics, in combination with both mitotic blockers and drivers, induced substantial cell death, mainly through apoptosis, in 2D and 3D cultures. Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness.
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SARS-CoV-2 transmission occurs mainly indoors, through virus-laden airborne particles. Although the presence and infectivity of SARS-CoV-2 in aerosol are now acknowledged, the underlying circumstances for its occurrence are still under investigation. The contamination of domiciliary environments during the isolation of SARS-CoV-2-infected patients in their respective rooms in individual houses and in a nursing home was investigated by collecting surface and air samples in these environments. Surface contamination was detected in different contexts, both on high and low-touch surfaces. To determine the presence of virus particles in the air, two sampling methodologies were used: air and deposition sampling. Positive deposition samples were found in sampling locations above the patient's height, and SARS-CoV-2 RNA was detected in impactation air samples within a size fraction below 2.5 µm. Surface samples rendered the highest positivity rate and persistence for a longer period. The presence of aerosolized SARS-CoV-2 RNA occurred mainly in deposition samples and closer to symptom onset. To evaluate the infectivity of selected positive samples, SARS-CoV-2 viability assays were performed, but our study was not able to validate the virus viability. The presented results confirm the presence of aerosolized SARS-CoV-2 RNA in indoor compartments occupied by COVID-19 patients with mild symptoms, in the absence of aerosol-generating clinical procedures.
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COVID-19 , SARS-CoV-2 , Humanos , ARN Viral/genética , Aerosoles y Gotitas RespiratoriasRESUMEN
BACKGROUND: Gold nanoparticles (AuNPs) can inhibit pivotal pathological changes in experimental asthma, but their effect on steroid-insensitive asthma is unclear. The current study assessed the effectiveness of nebulized AuNPs in a murine model of glucocorticoid (GC)-resistant asthma. METHODS: A/J mice were sensitized and subjected to intranasal instillations of ovalbumin (OVA) once a week for nine weeks. Two weeks after starting allergen stimulations, mice were subjected to Budesonide or AuNP nebulization 1 h before stimuli. Analyses were carried out 24 h after the last provocation. RESULTS: We found that mice challenged with OVA had airway hyperreactivity, eosinophil, and neutrophil infiltrates in the lung, concomitantly with peribronchiolar fibrosis, mucus production, and pro-inflammatory cytokine generation compared to sham-challenged mice. These changes were inhibited in mice treated with AuNPs, but not Budesonide. In the GC-resistant asthmatic mice, oxidative stress was established, marked by a reduction in nuclear factor erythroid 2-related factor 2 (NRF2) levels and catalase activity, accompanied by elevated values of thiobarbituric acid reactive substances (TBARS), phosphoinositide 3-kinases δ (PI3Kδ) expression, as well as a reduction in the nuclear expression of histone deacetylase 2 (HDAC2) in the lung tissue, all of which sensitive to AuNPs but not Budesonide treatment. CONCLUSION: These findings suggest that AuNPs can improve GC-insensitive asthma by preserving HDAC2 and NRF2.
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The SARS-CoV-2 pandemic emphasized effective cleaning and disinfection of common spaces as an essential tool to mitigate viral transmission. To address this problem, decontamination technologies based on UV-C light are being used. Our aim was to generate coherent and translational datasets of effective UV-C-based SARS-CoV-2 inactivation protocols for the application on surfaces with different compositions. Virus infectivity after UV-C exposure of several porous (bed linen, various types of upholstery, synthetic leather, clothing) and non-porous (types of plastic, stainless steel, glass, ceramics, wood, vinyl) materials was assessed through plaque assay using a SARS-CoV-2 clinical isolate. Studies were conducted under controlled environmental conditions with a 254-nm UV-C lamp and irradiance values quantified using a 254 nm-calibrated sensor. From each material type (porous/non-porous), a product was selected as a reference to assess the decrease of infectious virus particles as a function of UV-C dose, before testing the remaining surfaces with selected critical doses. Our data show that UV-C irradiation is effectively inactivating SARS-CoV-2 on both material types. However, an efficient reduction in the number of infectious viral particles was achieved much faster and at lower doses on non-porous surfaces. The treatment effectiveness on porous surfaces was demonstrated to be highly variable and composition-dependent. Our findings will support the optimization of UV-C-based technologies, enabling the adoption of effective customizable protocols that will help to ensure higher antiviral efficiencies.
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COVID-19 , SARS-CoV-2 , Desinfección/métodos , Humanos , Pandemias , Rayos Ultravioleta , Inactivación de VirusRESUMEN
The efficacy of antimitotics is limited by slippage, whereby treated cells arrested in mitosis exit mitosis without cell division and, eventually, escape apoptosis, constituting a serious resistance mechanism to antimitotics. Strategies to overcome slippage should potentiate the cancer cell killing activity of these antimitotics. Such strategies should accelerate cell death in mitosis before slippage. Here, we undertook a mechanistic analysis to test whether the apoptosis activator Navitoclax potentiates apoptosis triggered by the antimitotic BI2536, a potent inhibitor of Polo-like kinase 1 (PLK1) with the goal of overcoming slippage. We found that cancer cells in 2D cultures treated with BI2536 alone accumulate in mitosis, but a significant fraction of arrested cells undergo slippage and survive. Remarkably, combining BI2536 with Navitoclax dramatically reduces slippage, shifting the cell fate to accelerated death in mitosis. The results are confirmed in 3D spheroids, a preclinical system that mimics in vivo tumor drug responses. Importantly, in 3D spheroids, the effect of the BI2536/Navitoclax combination requires a lower therapeutic dosage of each drug, underlying its potential to improve the therapeutic index. Our results highlight the relevance of apoptosis potentiators to circumvent slippage associated with antimitotics. The combination of BI2536 with Navitoclax shows in vitro synergy/additive effect, which warrants further clinical research.
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The BUB3 protein plays a key role in the activation of the spindle assembly checkpoint (SAC), a ubiquitous surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis and, consequently, prevents chromosome mis-segregation and aneuploidy. Besides its role in SAC signaling, BUB3 regulates chromosome attachment to the spindle microtubules. It is also involved in telomere replication and maintenance. Deficiency of the BUB3 gene has been closely linked to premature aging. Upregulation of the BUB3 gene has been found in a variety of human cancers and is associated with poor prognoses. Here, we review the structure and functions of BUB3 in mitosis, its expression in cancer and association with survival prognoses, and its potential as an anticancer target.
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BACKGROUND: Aquaporins are membrane channels responsible for the bidirectional transfer of water and small non-charged solutes across cell membranes. AQP3 and AQP5 are overexpressed in pancreatic ductal adenocarcinoma, playing key roles in cell migration, proliferation, and invasion. Here, we evaluated AQP3 and AQP5 involvement in cell biomechanical properties, cell-cell adhesion, and cell migration, following a loss-of-function strategy on BxPC-3 cells. RESULTS: Silencing of AQP3 and AQP5 was functionally validated by reduced membrane permeability and had implications on cell migration, slowing wound recovery. Moreover, silenced AQP5 and AQP3/5 cells showed higher membrane fluidity. Biomechanical and morphological changes were assessed by atomic force microscopy (AFM), revealing AQP5 and AQP3/5 silenced cells with a lower stiffness than their control. Through cell-cell adhesion measurements, the work (energy) necessary to detach two cells was found to be lower for AQP-silenced cells than control, showing that these AQPs have implications on cell-cell adhesion. CONCLUSION: These findings highlight AQP3 and AQP5 involvement in the biophysical properties of cell membranes, whole cell biomechanical properties, and cell-cell adhesion, thus having potential implication in the settings of tumor development.
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Acuaporina 3 , Acuaporina 5 , Neoplasias Pancreáticas , Acuaporina 3/genética , Acuaporina 3/metabolismo , Acuaporina 5/genética , Acuaporina 5/metabolismo , Adhesión Celular , Movimiento Celular , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias PancreáticasRESUMEN
Nipah virus (NiV) is a recently emerging zoonotic virus that belongs to the Paramyxoviridae family and the Henipavirus genus. It causes a range of conditions, from asymptomatic infection to acute respiratory illness and fatal encephalitis. The high mortality rate of 40 to 90% ranks these viruses among the deadliest viruses known to infect humans. Currently, there is no antiviral drug available for Nipah virus disease and treatment is only supportive. Thus, there is an urgent demand for efficient antiviral therapies. NiV F protein, which catalyzes fusion between the viral and host membranes, is a potential target for antiviral drugs, as it is a key protein in the initial stages of infection. Fusion inhibitor peptides derived from the HRC-domain of the F protein are known to bind to their complementary domain in the protein's transient intermediate state, preventing the formation of a six-helix bundle (6HB) thought to be responsible for driving the fusion of the viral and cell membranes. Here, we evaluated the biophysical and structural properties of four different C-terminal lipid-tagged peptides. Different compositions of the lipid tags were tested to search for properties that might promote efficacy and broad-spectrum activity. Fluorescence spectroscopy was used to study the interaction of the peptides with biomembrane model systems and human blood cells. In order to understand the structural properties of the peptides, circular dichroism measurements and molecular dynamics simulations were performed. Our results indicate a peptide preference for cholesterol-enriched membranes and a lipid conjugation-driven stabilization of the peptide α-helical secondary structure. This work may contribute for the development of highly effective viral fusion against NiV inhibitors.
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[This corrects the article DOI: 10.3389/fonc.2021.752127.].
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BACKGROUND: Complete spinal cord injury (SCI) is characterized by permanent loss of nerve impulse propagation through the injury level leading to complete loss of voluntary muscle contraction. However, clinically undetectable top-down modulation of lower limbs might be present and can be evidenced using surface electromyography (sEMG). CASE REPORT: A subject with complete chronic SCI and no spasticity presents voluntary modulation of sEMG signal during a task-specific activity associated with sensory input. CLINICAL REHABILITATION IMPACT: We present for the first time the spectral characterization of sEMG signal in response to orthostatic training associated with voluntary movement attempts in complete SCI. Behavior of sEMG signal varied according to kinematic properties of movement, reinforcing the voluntary influence of efferent pathways on motor output. Our findings will contribute to elaborate evaluation protocols to investigate the preservation of corticospinal activities, and to evolve more accessible strategies in a clinical setting.
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Traumatismos de la Médula Espinal , Electromiografía/métodos , Humanos , Movimiento , Contracción Muscular , Espasticidad Muscular/complicaciones , Músculo Esquelético/fisiología , Traumatismos de la Médula Espinal/rehabilitaciónRESUMEN
Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.