The treatment with chemotherapy may develop secondary tumors as a result of chemo genotoxicity. Sperm defects is another complication associated with chemo treatment. In this study the genotoxicity of vinblastine (VB) was estimated in both somatic and germ cells.

Neurotoxicity of anticancer drugs complicates treatment of cancer patients. Vinblastine (VBL) is reported to induce motor and cognitive impairments in patients receiving chronic low-dose regimen.

Microtubule-targeting agents (MTAs), widely used as biological probes and chemotherapeutic drugs, bind directly to tubulin subunits and "kinetically stabilize" microtubules, suppressing the characteristic self-assembly process of dynamic instability. However, the molecular-level mechanisms of kinetic stabilization are unclear, and the fundamental thermodynamic and kinetic requirements for dynamic instability and its elimination by MTAs have yet to be defined. Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap.

Vinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.

In recent years, studies on the effects of combining novel plant compounds with cytostatics used in cancer therapy have received considerable attention. Since emodin sensitizes tumor cells to chemotherapeutics, we evaluated changes in cervical cancer cells after its combination with the antimitotic drug vinblastine. Cellular changes were demonstrated using optical, fluorescence, confocal and electron microscopy. Cell viability was assessed by MTT assay. The level of apoptosis, caspase 3/7, Bcl-2 protein, ROS, mitochondrial membrane depolarization, cell cycle and degree of DNA damage were analyzed by flow cytometry. The microscopic image showed indicators characteristic for emodin- and vinblastine-induced mitotic catastrophe, i.e., multinucleated cells, giant cells, cells with micronuclei, and abnormal mitotic figures. These compounds also increased blocking of cells in the G2/M phase, and the generated ROS induced swelling and mitochondrial damage. This translated into the growth of apoptotic cells with active caspase 3/7 and inactivation of Bcl-2 protein and active ATM kinase. Emodin potentiated the cytotoxic effect of vinblastine, increasing oxidative stress, mitotic catastrophe and apoptosis. Preliminary studies show that the combined action of both compounds, may constitute an interesting form of anticancer therapy.

Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo.

Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.

Vinblastine (VLB) is an antimitotic drug that binds to the vinca site of tubulin. The molecule possesses a high molecular weight and a complex chemical structure with many possibilities of metabolization. Despite advances in drug discovery research in reducing drug toxicity, the cause and mechanism of VLB-induced adverse drug reactions (ADRs) remains poorly understood. VLB is metabolized to at least 35 known metabolites, which have been identified and collected in this present work. This study also explores how VLB metabolites affect nausea-associated receptors such as muscarinic, dopaminergic, and histaminic. The metabolites have stronger binding interactions than acetylcholine (ACh) for muscarinic M1, M4, and M5 receptors and demonstrate similar binding profiles to that of the natural substrate, ACh. The affinities of VLB metabolites to dopaminergic and histaminic receptors, their absorption, distribution, metabolism, excretion, toxicity properties, and the superiority of VLB to ACh for binding to M5R, indicate their potential to trigger activation of nausea-associated receptors during chemotherapy with VLB. It has been shown that metabolite 20-hydroxy-VLB (metabolite 10) demonstrates a stronger binding affinity to the vinca site of tubulin than VLB; however, they have similar modes of action. VLB and metabolite 10 have similar gastric solubility (FaSSGF), intestinal solubility (FeSSIF), and log P values. Metabolite 10 has a more acceptable pharmacokinetic profile than VLB, a better gastric and intestinal solubility. Furthermore, metabolite 10 was found to be less bound to plasma proteins than VLB. These are desired and essential features for effective drug bioavailability. Metabolite 10 is not a substrate of CYP2D6 and thus is less likely to cause drug-drug interactions and ADRs compared to its parent drug. The hydroxyl group added upon metabolism of VLB suggests that it can also be a reasonable starting compound for designing the next generation of antimitotic drugs to overcome P-glycoprotein-mediated multidrug resistance, which is often observed with vinca alkaloids.

Effective therapies for transitional cell carcinoma (TCC) are limited, with objective response rates to most chemotherapeutic regimens below 20%. The purpose of this study was to investigate the biologic activity of combined toceranib phosphate and vinblastine chemotherapy for treatment of TCC. A secondary objective was to compare the utility of Computed Tomography (CT) and abdominal ultrasound (AUS) in tumor response assessments.

We have shown previously that in KB-3 (HeLa) cells vinblastine causes downregulation of the CDK inhibitor p21 through a c-Jun regulated pathway. To test the hypothesis that p21 downregulation is necessary to alleviate a protective function, we transfected p21 in KB-3 cells and examined the apoptotic response to vinblastine. The results showed that cells overexpressing p21 were apoptosis-resistant, not through an ability of p21 to cause cell cycle arrest prior to mitotic arrest, but through altering the fate of mitotically arrested cells after drug treatment. Moreover, p21 null HCT116 cells were more prone to vinblastine-induced apoptosis relative to wild-type cells. The results provide support for a model whereby p21 downregulation promotes vinblastine-induced apoptosis by alleviating its protective function following mitotic arrest.

Vinblastine (VBL) is a major chemotherapeutic drug; however, in some cases, it may cause severe side effects in patients with cancer. Designing a novel VBL pharmaceutical formulation is a crucial and emerging concern among researchers for reducing the use of VBL. This study developed a stimuli-responsive controlled VBL drug release system from magnetically sensitive chitosan capsules. A magnetically responsive controlled drug release system was designed by embedding superparamagnetic iron oxide (SPIO) nanoparticles (NPs) in a chitosan matrix and an external magnet. In addition, droplet microfluidics, which is a novel technique for producing polymer spheres, was used for manufacturing monodispersed chitosan microparticles. The prepared VBL and SPIO NPs-loaded chitosan microparticles were characterized and analyzed using Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, a superconducting quantum interference device, and a biocompatibility test. The drug encapsulation efficiency was 67%-69%. The in vitro drug release test indicated that the VBL could be 100% released from chitosan composite particles in 80-130 min under magnetic stimulation. The pulsatile magnetically triggered tests showed individual and distinctive controlled release patterns. Thus, the timing and dose of VBL release was controllable by an external magnet. The results presume that using a magnetically responsive controlled drug release system offers a valuable opportunity for VBL drug delivery, where the delivery system is an active participant, rather than a passive vehicle, in the optimization of cancer treatment. The proposed actively targeted magnetic drug delivery system offers many advantages over conventional drug delivery systems by improving the precision and timing of drug release, easy operation, and higher compliance for pharmaceutical applications.

Chemoresistance remains the main causes of treatment failure and mortality in cancer patients. There is an urgent need to investigate novel approaches to improve current therapeutic modalities and increase cancer patients' survival. Induction of drug efflux due to overexpression of P-glycoproteins is considered as an important leading cause of multidrug resistance. In this study, we investigated the role of combination treatments of docetaxel and vinblastine in overcoming P-glycoprotein mediated inhibition of apoptosis and induction of cell proliferation in human non-small cell lung carcinoma cells.

Vinblastine is a vinca alkaloid that binds to tubulin and inhibits microtubule formation in cells. Vinblastine treatment results in the formation of paracrystalline aggregates in the cells, which are formed from tightly packed tubulin molecules. Mitotic spindle assemblies in treated cells are disrupted and cell cycle progression is arrested at the mitosis phase. Vinblastine is therefore widely used for cancer treatment. However, the mechanism underlying paracrystal formation has not been fully elucidated. The present study attempted to observe paracrystal formation in human A549 cells. Initally, paracrystal formation was detected using the anti-tubulin antibody. Secondly, the exogenousuly expressed RFP-conjugated tubulin also formed paracrystals. Additionally, immunostaining with the anti-RBM8A antibody overlapped with paracrystal images obtained from RFP conjugated tubulin. This suggested that the localization of the RBM8A proteins was adjacent to the tubulin molecules prior to vinblastine treatment. Furthermore, a time-lapse analysis was developed for paracrystal formation in viable human A549 cells. This was achieved using exogenous expression of fluorescent proteins conjugated with tubulin and time-lapse microscopy. It may be concluded that the indicated method was successful for the real-time analysis of paracrystal formation in human cells.

Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response.

Human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs) are expected to be utilized in regenerative medicine. To perform a safe transplantation without the risk of tumor formation, residual undifferentiated hiPSCs must be removed from hiPSC-IECs. In this study, we examined whether vinblastine (a multiple drug resistance 1 [MDR1] substrate) could remove residual undifferentiated hiPSCs in hiPSC-IECs and attempted to generate hiPSC-IECs applicable to transplantation medicine. We found that the expression levels of pluripotent markers were largely decreased and those of intestinal markers were increased by vinblastine treatment. The treatment of undifferentiated hiPSCs with vinblastine significantly decreased their viability. These results suggested that undifferentiated hiPSCs can be eliminated from hiPSC-IECs by vinblastine treatment. We hypothesized that MDR1-negative cells (such as undifferentiated hiPSCs) die upon vinblastine treatment because they are unable to excrete vinblastine. As expected, the cell viability of MDR1-knockout hiPSC-IECs was significantly decreased by vinblastine treatment. Furthermore, teratomas were formed by subcutaneous transplantation of hiPSC-IECs mixed with undifferentiated hiPSCs into mice, but they were not observed when the transplanted cells were pre-treated with vinblastine. Vinblastine-treated hiPSC-IECs would be an effective cell source for safe regenerative medicine.

Many patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using vinblastine, since neuritis disrupts such processes.

This study aimed to evaluate the inhibitory effect of laetrile, vinblastine, and their mixture on cervical cancer cells and probe potential synergistic consequences.

Optimal chemotherapy protocols for high-risk mast cell tumours (MCTs) are unknown. The purpose of this study was to determine the tolerability and toxicity profile of a rapidly escalating vinblastine and prednisolone protocol (VPP) in which 3.00 mg/m2 was administered once 7 days apart: at day 14 and at day 21. Dogs with chemotherapy-naïve MCTs presenting to the Oncology Service of a single institution were prospectively enrolled to receive escalating vinblastine, and haematology and a standardised quality-of-life questionnaire were assessed prior to each dosage. Thirty-four dogs were included: 30 with microscopic disease treated with adequate local therapy and four with macroscopic disease. Of 220 doses of vinblastine administered, 4% were associated with grade 3 and 4 toxicity. A total of 70% of dogs tolerated 3.00 mg/m2 given 7 days apart at day 14 and 21, although 29% of dogs developed dose-limiting toxicities and 8% discontinued the protocol due to toxicity. In conclusion, VPP was well-tolerated overall, although prior to further dose intensity optimisation, it is important to determine if dose intensity is linked to outcome in canine MCT to avoid unwarranted toxicity.

During cancer treatment, doses must be carefully administered and monitored to guarantee efficacy and minimize side-effects. A potentiometric sensor was developed for the direct real-time assay of a widely used antineoplastic drug (vinblastine (VB)) in plasma samples. Membrane cocktails were drop-casted over a glassy-carbon electrode coated with a lipophilic conducting polymer (polyaniline). The study investigated five cation exchangers, five plasticizers (of different polarities and dielectric constants), and four ionophores with different physicochemical characters on the sensor performance. The study substantiates a data-driven selection of the optimum membrane recipe. The latter included sodium tetraphenylborate as an ion exchanger, dioctylphthalate as a plasticizer, and hydroxypropyl-β-cyclodextrin as ionophore. The membrane proved a near-Nernstian slope of 37.5 mV per decade, a LOQ of 2.99 × 10-6 M, and a stable fast response. The selectivity study proved poor responses to common physiological ions. The developed sensor was used for the determination of VB in its pure powder form, marketed formulation, and plasma samples. The fast and direct sensor response enables a wide range of applications in quality control laboratories and clinical studies.

In the present study, we developed chitosan/hyaluronan nanoparticles (CS/HY NPs) for tumor targeting with vinblastine sulfate (VBL), that can be directed to the CD44 transmembrane receptor, over-expressed in cancer cells. NPs were prepared by coating with HY-preformed chitosan/tripolyphosphate (CS/TPP) NPs, or by polyelectrolyte complexation of CS with HY. NPs with a mean hydrodynamic radius (RH) of 110 nm, 12% polydispersity index and negative zeta potential values were obtained by a direct complexation process. Transmission Electron Microscopy (TEM) images showed spherical NPs with a non-homogeneous matrix, probably due to a random localization of CS and HY interacting chains. The intermolecular interactions occurring between CS and HY upon NPs formation were experimentally evidenced by micro-Raman (µ-Raman) spectroscopy, through the analysis of the spectral changes of characteristic vibrational bands of HY during NP formation, in order to reveal the involvement of specific chemical groups in the process. Optimized NP formulation efficiently encapsulated VBL, producing a drug sustained release for 20 h. In vitro studies demonstrated a fast internalization of labeled CS/HY NPs (within 6 h) on K-562 human myeloid leukemia cells. Pre-saturation of CD44 by free HY produced a slowing-down of NP uptake over 24 h, demonstrating the need of CD44 for the internalization of HY-based NPs.