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Biochemical and Biophysical Research... Aug 2019We report the utility of cevipabulin as a stabilizing agent for microtubules. Cevipabulin-stabilized microtubules were more flexible compared to the microtubules...
We report the utility of cevipabulin as a stabilizing agent for microtubules. Cevipabulin-stabilized microtubules were more flexible compared to the microtubules stabilized by paclitaxel, the most commonly used microtubule stabilizing agent. Similar to the paclitaxel-stabilized microtubules, cevipabulin-stabilized microtubules were driven by kinesins in an in vitro gliding assay. The velocity of cevipabulin-stabilized microtubules was significantly higher than that of paclitaxel-stabilized microtubules. These findings will enrich the variety of microtubules with difference in mechanical and dynamic properties and widen their applications in nanotechnology.
Topics: Animals; Hydrocarbons, Halogenated; Microscopy, Fluorescence; Microtubules; Molecular Docking Simulation; Molecular Structure; Nanotechnology; Paclitaxel; Protein Stability; Swine; Time-Lapse Imaging; Triazoles; Tubulin
PubMed: 31253401
DOI: 10.1016/j.bbrc.2019.06.095 -
Drug Delivery Dec 2023Magnetic FeO nanoparticles were prepared via a simple hydrothermal method and utilized to load paclitaxel. The average particle size of FeO nanoparticles was found to be...
Magnetic FeO nanoparticles were prepared via a simple hydrothermal method and utilized to load paclitaxel. The average particle size of FeO nanoparticles was found to be 20.2 ± 3.0 nm, and the calculated saturation magnetization reached 129.38 emu/g, verifying superparamagnetism of nanomaterials. The specific surface area and pore volume were 84.756 m/g and 0.265 cm/g, respectively. Subsequently, FeO@mSiO nanoparticles were successfully fabricated using the FeO nanoparticles as precursors with an average size of 27.81 nm. The relevant saturation magnetization, zeta potential, and specific surface area of FeO@mSiO-NH-FA were respectively 76.3 emu/g, -14.1 mV, and 324.410 m/g. The pore volume and average adsorption pore size were 0.369 cm/g and 4.548 nm, respectively. Compared to free paclitaxel, the solubility and stability of nanoparticles loaded with paclitaxel were improved. The drug loading efficiency and drug load of the nanoformulation were 44.26 and 11.38%, respectively. The FeO@mSiO-NH-FA nanocomposites were easy to construct with excellent active targeting performance, pH sensitivity, and sustained-release effect. The nanoformulation also showed good biocompatibility, where the cell viability remained at 73.8% when the concentration reached 1200 μg/mL. The nanoformulation induced cell death through apoptosis, as confirmed by AO/EB staining and flow cytometry. Western blotting results suggested that the nanoformulation could induce iron death by inhibiting Glutathione Peroxidase 4 (GPX4) activity or decreasing Ferritin Heavy Chain 1 (FTH1) expression. Subsequently, the expression of HIF-1α was upregulated owing to the accumulation of reactive oxygen species (ROS), thus affecting the expression of apoptosis-related proteins regulated by p53, inducing cell apoptosis.
Topics: Humans; MCF-7 Cells; Paclitaxel; Magnetic Phenomena
PubMed: 36474448
DOI: 10.1080/10717544.2022.2154411 -
Pharmaceutical Development and... Jan 2022'One drug- one target' to 'multiple drug- multiple targets' paradigm shifted to produce combination therapies, have found great outcomes to overcome multiple drug... (Review)
Review
'One drug- one target' to 'multiple drug- multiple targets' paradigm shifted to produce combination therapies, have found great outcomes to overcome multiple drug resistance (MDR). MDR is a significant barrier to the delivery of taxane-based anticancer medicines such as docetaxel, paclitaxel, and cabazitaxel. Due to MDR induced by drug efflux transporters, clinical application of these medications is impeded. To date, nanoformulations such as liposomes, micelles, polymeric nanoparticles, and gold nanoparticles have been investigated to deliver taxanes alone and in combination to reverse drug resistance. Despite the fact that various groups have already looked into taxane nano formulations in the literature, there isn't much in the way of polypharmacology and advanced nanoformulations with a focus on MDR. In this overview, we briefly covered the insights regarding MDR, difficulties related to current pharmaceutical products of taxanes, combination therapies of taxanes to combat MDR, all of which can be used to delve into cancer treatment.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Gold; Metal Nanoparticles; Micelles; Nanotechnology; Neoplasms; Paclitaxel; Taxoids
PubMed: 34806547
DOI: 10.1080/10837450.2021.2009861 -
Acta Biomaterialia Jul 2023The combination of chemotherapy and photodynamic therapy (PDT) has the potential to complement single-drug therapies, but chemotherapeutic agents and photosensitizers...
The combination of chemotherapy and photodynamic therapy (PDT) has the potential to complement single-drug therapies, but chemotherapeutic agents and photosensitizers often have compromised therapeutic efficacies and strong toxic effects. In this study, we exploited nanotechnology to address this challenge by utilizing heparin as a carrier for co-delivery of chemotherapeutic drugs and photosensitizers for synergistic cancer therapy. Specifically, heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa) were synthesized by attaching paclitaxel (PTX), a small molecular chemotherapeutic drug, through a reactive oxygen species (ROS)-responsive linker and Ppa, a photosensitizer, to heparin, respectively. Two conjugates were co-assembled into a nanomedicine, HP-PP nanoparticles (NPs), for controllable co-delivery of Ppa and PTX into tumor cells. HP-PP NPs significantly enhanced the in vitro stability of HP-Ppa and the photostability of Ppa, and the synergistic actions of chemotherapy and PDT were confirmed by both in vitro and in vivo antitumor studies. Notably, HP-PP NPs enhanced tumor accumulation of Ppa up to 11-fold and the treatment of 4T1 tumor-bearing mice with HP-PP NPs resulted in a tumor growth inhibition of 98.1% without systemic toxicity. The strategy of co-assembly of heparin conjugates may offer great potential in enhancing the efficacy of combination therapy. STATEMENT OF SIGNIFICANCE: We proposed a nano-delivery system, HP-PP NPs, which was constructed by co-assembly of heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa), to co-deliver PTX and Ppa for synergistic cancer therapy. HP-PP NPs enhanced the photostability and the in vitro stability of Ppa and HP-Ppa, and induced greater cytotoxicity than HP-PTX NPs or HP-Ppa NPs. This co-delivery system displays enhanced tumor accumulation and has a remarkable synergistic antitumor effect with a tumor growth inhibition of 98.1%.
Topics: Animals; Mice; Pharmaceutical Preparations; Photosensitizing Agents; Drug Delivery Systems; Nanomedicine; Heparin; Cell Line, Tumor; Paclitaxel; Nanoparticles; Mice, Inbred BALB C; Neoplasms
PubMed: 37088159
DOI: 10.1016/j.actbio.2023.04.016 -
ELife Mar 2023Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the...
Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.9 Å resolution. Based on this information, we engineered taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects on microtubules (X-ray fiber diffraction), along with those of paclitaxel, docetaxel, and baccatin III. Further comparison of high-resolution structures and microtubules' diffractions with the apo forms and molecular dynamics approaches allowed us to understand the consequences of taxane binding to tubulin in solution and under assembled conditions. The results sheds light on three main mechanistic questions: (1) taxanes bind better to microtubules than to tubulin because tubulin assembly is linked to a βM-loopconformational reorganization (otherwise occludes the access to the taxane site) and, bulky C13 side chains preferentially recognize the assembled conformational state; (2) the occupancy of the taxane site has no influence on the straightness of tubulin protofilaments and; (3) longitudinal expansion of the microtubule lattices arises from the accommodation of the taxane core within the site, a process that is no related to the microtubule stabilization (baccatin III is biochemically inactive). In conclusion, our combined experimental and computational approach allowed us to describe the tubulin-taxane interaction in atomic detail and assess the structural determinants for binding.
Topics: Tubulin; Taxoids; Microtubules; Paclitaxel
PubMed: 36876916
DOI: 10.7554/eLife.84791 -
Chemical Reviews Apr 2023Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in... (Review)
Review
Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in the treatment of breast, lung, and ovarian cancers, saving countless lives around the world. Structurally, Taxol possesses a highly oxygenated [6-8-6-4] core bearing 11 stereocenters, seven of which are contiguous chiral centers. Moreover, the extremely strained bicyclo[5.3.1] undecane ring system with a bridgehead double bond is a unique structural feature. All these features make Taxol a highly challenging synthetic target. Tremendous synthetic efforts from more than 60 research groups around the world have already culminated in ten total syntheses and three formal syntheses, as well as more than 60 synthetic model studies of Taxol. This review is intended to provide a long-overdue appraisal of the great achievements in the total syntheses of Taxol reported in the last few decades. In doing so, we summarize the development of synthesis toward Taxol from 1994 to 2022, including the evolution of synthetic strategy for accessing this complex molecular scaffold and key lessons learned from such endeavors. Finally, we briefly discuss the future of the research in this area.
Topics: Paclitaxel; Antineoplastic Agents
PubMed: 36917457
DOI: 10.1021/acs.chemrev.2c00763 -
Biotechnology Advances Nov 2020Paclitaxel is one of the strong plant-derived anti-cancer drugs that was first isolated from the Pacific yew. Despite many paclitaxel's clinical successes, the limited... (Review)
Review
Paclitaxel is one of the strong plant-derived anti-cancer drugs that was first isolated from the Pacific yew. Despite many paclitaxel's clinical successes, the limited accessibility of paclitaxel for clinical trials is recognized as the most important challenge. Thus, researchers are continuously trying to find the innovative ways to meet the community's need for this medicine. In the first step, the alternative sources for Taxol supply were recognized, such as Taxus genus, other plant genera, and endophytic fungi. In the next step, the biosynthetic pathways of Taxol or related metabolites were manipulated in the original organisms, or introduced to heterologous systems and then were manipulated in them. Here, a range of metabolic manipulating approaches have been successfully developed to redirect the metabolic flux toward Taxol, including promoter engineering, enzyme engineering, overexpressing the bottleneck enzymes, over- or down-regulation of transcription factors, activation of the cryptic genes, removing/minimizing the flux for competing pathways, tunable regulation of the metabolic pathway, and increasing the supplies of precursors. In this review, we discuss research progress on the alternative Taxol sources and its metabolic manipulating, and we suggest recent challenges and future perspectives.
Topics: Biosynthetic Pathways; Fungi; Metabolic Engineering; Paclitaxel; Taxus
PubMed: 32446923
DOI: 10.1016/j.biotechadv.2020.107569 -
Molecules (Basel, Switzerland) Apr 2023Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity...
Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity of paclitaxel in several aminopolycarboxylic acid groups. In this study, the in vitro and in vivo antitumor effects and mechanisms of PTX-TTHA against triple-negative breast cancer (TNBC) and its intravenous toxicity were evaluated. Results showed the water solubility of PTX-TTHA was greater than 5 mg/mL, which was about 7140-fold higher than that of paclitaxel (<0.7 µg/mL). PTX-TTHA (10-10 nmol/L) could significantly inhibit breast cancer proliferation and induce apoptosis by stabilizing microtubules and arresting the cell cycle in the G2/M phase in vitro, with its therapeutic effect and mechanism similar to paclitaxel. However, when the MDA-MB-231 cell-derived xenograft (CDX) tumor model received PTX-TTHA (13.73 mg/kg) treatment once every 3 days for 21 days, the tumor inhibition rate was up to 77.32%. Furthermore, PTX-TTHA could inhibit tumor proliferation by downregulating Ki-67, and induce apoptosis by increasing pro-apoptotic proteins (Bax, cleaved caspase-3) and TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and reducing anti-apoptotic protein (Bcl-2). Moreover, PTX-TTHA demonstrated no sign of acute toxicity on vital organs, hematological, and biochemical parameters at the limit dose (138.6 mg/kg, i.v.). Our study indicated that PTX-TTHA showed better water solubility than paclitaxel, as well as comparable in vitro and in vivo antitumor activity in TNBC models. In addition, the antitumor mechanism of PTX-TTHA was related to microtubule regulation and apoptosis signaling pathway activation.
Topics: Humans; Paclitaxel; Triple Negative Breast Neoplasms; Cell Cycle; Water; Cell Line, Tumor; Apoptosis
PubMed: 37175072
DOI: 10.3390/molecules28093662 -
Cancer Dec 2019According to the statement from the 5th Ovarian Cancer Consensus Conference in 2015, the primary systemic chemotherapy for advanced ovarian cancer is a combination of... (Review)
Review
According to the statement from the 5th Ovarian Cancer Consensus Conference in 2015, the primary systemic chemotherapy for advanced ovarian cancer is a combination of paclitaxel plus carboplatin administered every 3 weeks (PCq3w). Optional alternatives include weekly dose-dense paclitaxel, in combination and maintenance therapy with bevacizumab, and intraperitoneal chemotherapy. Since then, in addition to the PCq3w strategy, there has been emerging new evidence, especially for poly(adenosine diphosphate-ribose) polymerase inhibitors. Moreover, there are multiple randomized, phase 3 trials testing the addition of antiangiogenic and/or immune checkpoint inhibitors in this patient population. In this article, current and future perspectives of systemic chemotherapy for advanced ovarian cancer are discussed.
Topics: Antineoplastic Agents, Phytogenic; Female; History, 20th Century; Humans; Ovarian Neoplasms; Paclitaxel
PubMed: 31967679
DOI: 10.1002/cncr.32475 -
European Journal of Medicinal Chemistry Apr 2022In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded...
In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded in cationic liposomes (CTL), which exhibited a substantial enhanced permeability and retention effect (EPR effect) in breast cancer. CTL containing crizotinib and paclitaxel (CRI-PTX-CTL) had particle sizes of (138.63 ± 1.53) nm and zeta potentials of (50.90 ± 0.30) mV, respectively. It was spherical and uniformly dispersed under TEM. The in vitro release of CRI-PTX-CTL showed that the cumulative release rates of CRI and PTX within 12 h were 64.37% and 54.71%, and released from liposomes at the same time. At the cellular level, CRI and PTX were discovered to have synergistic effects. Cell uptake experiments demonstrated that CRI, PTX, and siRNA contained in CTL can be effectively taken up by MCF-7 cells. It was further proved that CTL-siRNA could effectively inhibit the expression of Bcl-xL in cells. CRI, PTX and Bcl-xL siRNA delivered by CTL showed enhanced cytotoxicity during in vitro experiments. Therefore, this study proved that the CRI-PTX-CTL-siRNA was a very promising delivery system for the treatment of breast cancer.
Topics: Breast Neoplasms; Cell Line, Tumor; Female; Humans; Liposomes; Paclitaxel; RNA, Small Interfering
PubMed: 35245829
DOI: 10.1016/j.ejmech.2022.114198