epothilone D (BMS-241027) / BMS - LARVOL DELTA

Nanoparticle and epothilone D combinatorial intervention improves motor performance and regeneration in chronic cervical spinal cord injury. (PubMed, Neurotherapeutics) - "In conjunction with this improved performance, mice that received NPs or epoD exhibited increased neuromuscular junction innervation, robust axon growth into the bridge, and both oligodendrocyte and Schwann-cell myelination of regenerating axons. Collectively, these results suggest that a combinatorial treatment plan targeting inflammation and scarring, a substrate for growth, and growth-promoting factors can improve motor performance following SCI."

Journal • CNS Disorders • Fibrosis • Inflammation • Orthopedics • Solid Tumor

Competition for microtubule lattice spacing between a microtubule expander and compactor. (PubMed, Curr Biol) - "To better understand how these opposing forces are reconciled, we developed in vitro and cell-based model systems for the competition between a microtubule expander (paclitaxel) and a microtubule compactor (doublecortin or DCX)...We conclude that multiple lattice spacings can coexist in cells. Our results indicate that competition for microtubule lattice spacing is a critical aspect of microtubule physiology."

Journal • DCX

Efficacy and safety of utidelone in pretreated patients with metastatic breast cancer in China: a multicenter, real-world study. (PubMed, Ther Adv Med Oncol) - "Utidelone (UTD1), a genetically engineered epothilone derivative, has been approved in China for use in combination with capecitabine in treating metastatic breast cancer (MBC) patients previously treated with anthracyclines or taxanes. Patients with unresolved PN from previous therapy or receiving UTD1 through intravenous infusion on days 1-5 were more likely to develop ⩾grade 3 PN. UTD1 is a new option for patients who have previously received taxanes and anthracyclines, with its clinical toxicity controllable."

Journal • Real-world evidence • Breast Cancer • Oncology • Pain • Solid Tumor

Microtubule Integrity Is Associated with Mitochondrial Function and Quality of Murine Preimplantation Embryos. (PubMed, Int J Mol Sci) - "In the present study, we investigated the effects of the microtubule stabilizers (MTS) Taxol and Epothilone D (EpD) and the microtubule disturber (MTD) vinorelbine on mouse preimplantation embryo quality and pregnancy outcome compared with non-treatment controls. Consistently, delivery ratios were significantly higher after transplantation with MTS-treated embryos than after transplantation with untreated embryos. These findings suggest that MTS could be used to supplement in vitro culture media to promote the recovery of poor-quality embryos."

Journal • Preclinical • Transplantation

Microtubule-modulating drugs alter sensitivity to isoflurane in mice. (PubMed, BMC Anesthesiol) - "Microtubule-modulating drugs can affect not only sensitivity but also induction and emergence times to inhalational anesthetic isoflurane in mice. This study highlights a possible role of MTDs in modulating anesthetic effects in disparate directions, which has implications for anesthetic concentrations that should be used for induction, maintenance and emergence of anesthesia. These findings in rodents may have relevance to the perioperative care of cancer patients who receive MT-targeting chemotherapy drugs or even opioids for pain for prolonged periods."

Journal • Preclinical • Anesthesia • Oncology • Pain

Effects of Epothilone D on Social Defeat Stress-induced Changes in Microtubule-related and Endoplasmic Reticulum Stress Protein Expression. (PubMed, Clin Psychopharmacol Neurosci) - "Our results suggest that EpoD exhibits a dual impact, manifesting both beneficial and detrimental effects on the aberrant changes of MT-related proteins and ER stress proteins induced by SDS, depending on the brain regions. These findings underscore the complexity of EpoD's effects, necessitating further exploration to understand its intricate mechanisms in cellular pathways linked to SDS."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia • HSPA5 • STMN1

Nanoparticle and epothilone D intervention improves motor performance and regeneration in chronic cervical spinal cord injury (Neuroscience 2024) - "Underlying this performance, all mice that received NPs or epoD exhibited robust axon growth into the injury and both oligodendrocyte and Schwann cell myelination of regenerating axons. Together, these results suggest that a combinatorial treatment plan that targets both inflammation and growth-inhibitory factors can improve motor performance following SCI."

Late-breaking abstract • CNS Disorders

Bioprocessing of Epothilone B from Aspergillus fumigatus under solid state fermentation: Antiproliferative activity, tubulin polymerization and cell cycle analysis. (PubMed, BMC Microbiol) - "Epothilone derivatives have been recognized as one of the most powerful anticancer drugs towards solid tumors, for their unique affinity to bind with β-tubulin microtubule arrays, stabilizing their disassembly, causing cell death...The purified A. fumigatus epothilone had a significant activity towards HepG2 (IC 0.98 μg/ml), Pancl (IC 1.5 μg/ml), MCF7 (IC 3.7 μg/ml) and WI38 (IC 4.6 μg/ml), as well as a strong anti-tubulin polymerization activity (IC 0.52 μg/ml) compared to Paclitaxel (2.0 μg/ml). The effect of A. fumigatus epothilone on the immigration ability of HepG2 cells was assessed, as revealed from the wound closure of the monolayer cells that was estimated by ~ 63.7 and 72.5%, in response to the sample and doxorubicin, respectively, compared to negative control. From the Annexin V-PI flow cytometry results, a significant shift of the normal cells to the apoptosis was observed in response to A. fumigatus epothilone by ~ 20 folds compared to control cells, with..."

Journal • Oncology • Solid Tumor • ANXA5

Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis. (PubMed, Acc Chem Res) - "For example, in the total syntheses of Quercuslactones, Helicascolides A-C, Epothilone D, Homolargazole, and Thailandepsin B, the Rh-catalyzed hydro-oxycarbonylation of allenes was used as key step via C-O bond formation...For the total syntheses of Centrolobine, Pitavastatin, and Rosuvastatin, C-O bond formation was achieved through the addition of a hydroxy function to the allene moiety. The potential of the addition of nitrogen pronucleophiles to allenes was demonstrated in the total syntheses of Cusparein, Angusterein, Cermicin C, Senepodin G, Homoproline, Pipecolinol, Coniceine, Coniine, Ruxolitinib, Sitagliptin, Abacavir, Glucokinase activators, and Chaetominine. All of these examples testify to the wide applicability of the Rh-catalyzed addition of pronucleophiles to allenes or alkynes in target-oriented synthesis, and in this Account we summarize our contribution."

Journal

Deleterious and protective effects of epothilone-D alone and in the context of amyloid β- and tau-induced alterations. (PubMed, Front Mol Neurosci) - "However, Epo-D also exhibited some side effects depending on the prevailing pathological or physiological condition, which should be considered in future preclinical and translational studies. Although we did not perform extensive histopathological evaluations or measured microtubule stability, our findings show that MSAs can rescue the consequences of AD-like conditions but otherwise be harmful if administered at a prodromal stage of the disease."

Journal • Alzheimer's Disease • CNS Disorders

Microtubule-stabilizing Drug Epothilone D Protects Mice From Angiotensin II-induced Abdominal Aortic Aneurysmal Rupture (VASCULAR DISCOVERY 2023) - "These findings demonstrate that microtubule stabilization by EpoD significantly suppresses AngII-induced AAA rupture without influencing AAA formation in mice."

Preclinical • Cardiovascular

A Study of Epothilone D in Combination With Herceptin (Trastuzumab) in Patients With HER-2 Positive Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=27 | Completed | Sponsor: Hoffmann-La Roche | Phase classification: P2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Epothilones as Natural Compounds for Novel Anticancer Drugs Development. (PubMed, Int J Mol Sci) - "There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury. (PubMed, Brain Commun) - "Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting."

Journal • CNS Disorders • Fibrosis • Orthopedics • FN1

The Improvement of Epothilone D Yield by the Disruption of epoK Gene in Sorangium cellulosum Using TALEN System. (PubMed, Mol Biotechnol) - "Epothlione D shows better drug resistance and safety than taxol in clinical trials. The qRT-PCR analysis and sequencing were performed to confirm the gene deletion of epoK, resulting in the epothilone D yield improvement by 34.9±1.6% and the decrease of epothilone B yield by 34.2±2.5%, which was demonstrated by LC-MS analysis. This study would lay a foundation for the yield improvement of epothilones D, B and thereof derivatives in S. cellulosum by genetic engineering, thus promoting the applications of epothilones in the field of anticancer."

Journal • Oncology

Amyloid beta and tau pathology induced alterations on spatial memory and hippocampal physiology can be reversed by a microtubule stabilizer (Neuroscience 2022) - "Here, we analyzed the spatial memory with the Hebb-Williams maze (H-WM) and the intrinsic and synaptic properties of CA1 pyramidal neurons (CA1-PN) with whole-cell recordings of WT and rTg4510 mice in the presence or absence of Aβ and a MSA (epothilone D)...Overall, Aβ and hyperphosphorylated tau produce divergent effects on intrinsic and synaptic properties that are, nevertheless, associated with memory retrieval deficits. Moreover, we showed that despite MSAs can prevent the deleterious effects of Aβ and tau, which further supports its use to treat AD, it must be acknowledged that they can produce negative effects on behavior and brain function, highlighting the need for more research of their potential clinical use."

Alzheimer's Disease • CNS Disorders

Super-resolution imaging and quantitative analysis of microtubule arrays in model neurons show that epothilone D increases the density but decreases the length and straightness of microtubules in axon-like processes. (PubMed, Brain Res Bull) - "Our data show that super-resolution imaging of microtubules followed by algorithm-based image analysis represents a powerful tool to quantitatively assess changes in microtubule organization in neuronal processes, useful to determine the effect of microtubule-modulating conditions. We also provide evidence that the approach is robust and can be applied to neuronal cell lines or primary neurons, both after incorporation of labeled tubulin and by anti-tubulin antibody staining."

Journal • Review • CNS Disorders

Effective Cancer Management: Inimitable Role of Phytochemical Based Nano-Formulations. (PubMed, Curr Drug Metab) - "The present review highlights the phytochemical-based nanoformulations and its strategies in the development of novel systems of drug delivery such as nano-liposomes, functionalized nanoparticles (NPs), and polymer nano-conjugates, SNEDDS (Self nano emulsifying drug delivery system) as this review paper depicts, as well as their rewards over conventional systems of drug delivery, as evidenced by improved biological activity depicted in their in vitro and in vivo anticancer assays."

Journal • Oncology

Manganese-enhanced magnetic resonance imaging method detects age-related impairments in axonal transport in mice and attenuation of the impairments by a microtubule-stabilizing compound. (PubMed, Brain Res) - "Moreover, in aged mice, eight weeks of treatment with Epothilone D, (0.3 and 1.0 mg/kg) was associated with statistically significant increases in AXT rates compared to vehicle-treated subjects. These experiments conducted in a living mammalian model (i.e., wild type, C57BL/6 mice), using a new modified MEMRI method, thus provide further evidence that the process of aging leads to decreases in AXT rates in the brain and they further support the argument that microtubule-based therapeutic strategies designed to improve AXT rates have potential for age-related neurological disorders."

Journal • MRI • Preclinical • Alzheimer's Disease • CNS Disorders

Protective effect of Epothilone D against traumatic optic nerve injury in rats (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "Epothilone D treatment can protect against TON in rats by promoting the survival of injured RGCs, enhancing Tau content in the surviving RGCs, reducing Tau accumulation in injured axons, and stimulating sustained regeneration of axons."

Clinical • Journal • Preclinical • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain

Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport. (PubMed, Mol Psychiatry) - "The microtubule-targeting drug Epothilone D normalized the interaction of TauC3 with microtubules and modulated the transport of APP-vesicles dependent on the presence of overexpressed human tau. The results indicate a novel toxic gain of function, in which a post-translational modification of tau changes the dynamics of the tau-microtubule interaction and thus leads to axonal transport defects and neuronal degeneration. The data also introduce microtubule-targeting drugs as pharmacological modifiers of the tau-microtubule interaction with the potential to restore the physiological interaction of pathologically altered tau with microtubules."

Journal • Alzheimer's Disease • CNS Disorders • CASP3 • MAPT

Epothilone D modulates autism-like behaviors in the BTBR mouse model of autism spectrum disorder. (PubMed, Neuroscience) - "Furthermore, studies have shown that Epothilone D, a taxol-like microtubule-stabilizing agent, could alleviate behavioral and synaptic deficits in STOP-null mice. Our studies demonstrated that the restrictive repetitive behaviors of BTBR mice were improved after Epothilone D treatment, which could be achieved by improving microtubule stability and further regulating the expression of excitatory synapse-related and myelin-related proteins. These results indicate that microtubule stability may be a new and promising therapeutic target for treating patients with ASD."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Psychiatry

Microtubule Integrity Is Associated with the Functional Activity of Mitochondria in HEK293. (PubMed, Cells) - "We treated HEK293 cells with microtubule stabilizers (Taxol and Epothilone D) or a microtubule disturber (vinorelbine), and performed live-cell imaging to determine whether mitochondrial morphology and bioenergetic activity depend on the microtubule status. Our data suggest that microtubule stability promotes mitochondrial functional activity. In conclusion, a microtubule stabilizer can possibly recover mitochondrial functional activity in cells with unstable microtubules."

Journal

Ixabepilone: Overview of Effectiveness, Safety, and Tolerability in Metastatic Breast Cancer. (PubMed, Front Oncol) - "While chemotherapy and endocrine therapy form the backbone of treatment for metastatic breast cancer, the epothilone drug class has distinguished itself for efficacy and safety among patients with disease progression during treatment with chemotherapy. Dose reductions did not appear to have an impact on the efficacy of ixabepilone plus capecitabine. Incorporation of ixabepilone into individualized treatment plans can extend progression-free survival in a patient population that continues to represent an unmet need."

Clinical • Journal • Review • Breast Cancer • Oncology • Pain • Solid Tumor • Triple Negative Breast Cancer

Upregulation of Apol8 by Epothilone D facilitates the neuronal relay of transplanted NSCs in spinal cord injury. (PubMed, Stem Cell Res Ther) - "Epothilone D can promote the neuronal differentiation of NSCs by upregulating Apol8, which may provide a promising therapeutic target for SCI repair."

Journal • CNS Disorders • Complement-mediated Rare Disorders • Orthopedics • Transplantation • PCR