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Experimental Neurology Jan 2023Paclitaxel is a common chemotherapeutic agent widely used to treat solid cancer. However, it frequently causes peripheral sensory neuropathy, resulting in sensory... (Review)
Review
Paclitaxel is a common chemotherapeutic agent widely used to treat solid cancer. However, it frequently causes peripheral sensory neuropathy, resulting in sensory abnormalities and pain in patients receiving treatment for cancer. As one of the most widely used chemotherapeutics, many preclinical studies on paclitaxel-induced peripheral neuropathy (PIPN) have been performed. Yet, there remain no effective options for treatment or prevention. Due to paclitaxel's ability to bind to and stabilize microtubules, a change in microtubule dynamics and subsequent disruptions in axonal transport has been predicted as a major underlying cause of paclitaxel-induced toxicity. However, the systemic understanding of PIPN mechanisms is largely incomplete, and various phenotypes have not been directly attributed to microtubule-related effects. This review aims to provide an overview of the literature involving paclitaxel-induced alteration in microtubule dynamics, axonal transport, and endocytic changes. It also aims to provide insights into how the microtubule-mediated hypothesis may relate to various phenotypes reported in PIPN studies.
Topics: Humans; Paclitaxel; Axonal Transport; Peripheral Nervous System Diseases; Microtubules; Axons
PubMed: 36279934
DOI: 10.1016/j.expneurol.2022.114258 -
Cancer Letters Apr 2024Given the limitations of the response rate and efficacy of immune checkpoint inhibitors (ICIs) in clinical applications, exploring new therapeutic strategies for cancer...
Given the limitations of the response rate and efficacy of immune checkpoint inhibitors (ICIs) in clinical applications, exploring new therapeutic strategies for cancer immunotherapy is necessary. We found that 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl)imidazole (BZML), a microtubule-targeting agent, exhibited potent anticancer activity by inducing mitotic catastrophe in A549/Taxol and L929 cells. Nuclear membrane disruption and nuclease reduction provided favorable conditions for cGAS-STING pathway activation in cells with mitotic catastrophe. Similar results were obtained in paclitaxel-, docetaxel- and doxorubicin-induced mitotic catastrophe in various cancer cells. Notably, the surface localization of CALR and MHC-I and the release of HMGB1 were also significantly increased in cells with mitotic catastrophe, but not in apoptotic cells, suggesting that mitotic catastrophe is an immunogenic cell death. Furthermore, activated CD8T cells enhanced the anticancer effects originating from mitotic catastrophe induced by BZML. Inhibiting the cGAS-STING pathway failed to affect BZML-induced mitotic catastrophe but could inhibit mitotic catastrophe-mediated anticancer immune effects. Interestingly, the expression of p-TBK1 first increased and then declined; however, autophagy inhibition reversed the decrease in p-TBK1 expression and enhanced mitotic catastrophe-mediated anticancer immune effects. Collectively, the inhibition of autophagy can potentiate mitotic catastrophe-mediated anticancer immune effects by regulating the cGAS-STING pathway, which explains why the anticancer immune effects induced by chemotherapeutics have not fully exerted their therapeutic efficacy in some patients and opens a new area of research in cancer immunotherapy.
Topics: Humans; Paclitaxel; Nucleotidyltransferases; Cell Death; Immunity; Autophagy
PubMed: 38325769
DOI: 10.1016/j.canlet.2024.216695 -
Anti-cancer Agents in Medicinal... 2020Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high... (Review)
Review
BACKGROUND
Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high cytotoxicity to normal tissue and worse pharmacokinetic property limit its clinical application.
OBJECTIVE
To review the recent progress on the PTX delivery systems.
METHODS
In recent years, the copolymeric nano-drug delivery systems for PTX are broadly studied. It mainly includes micelles, nanoparticles, liposomes, complexes, prodrugs and hydrogels, etc. They were developed or further modified with target molecules to investigate the release behavior, targeting to tissues, pharmacokinetic property, anticancer activities and bio-safety of PTX. In the review, we will describe and discuss the recent progress on the nano-drug delivery system for PTX since 2011.
RESULTS
The water-solubility, selective delivery to cancers, tissue toxicity, controlled release and pharmacokinetic property of PTX are improved by its encapsulation into the nano-drug delivery systems. In addition, its activities against cancer are also comparable or high when compared with the commercial formulation.
CONCLUSION
Encapsulating PTX into nano-drug carriers should be helpful to reduce its toxicity to human, keeping or enhancing its activity and improving its pharmacokinetic property.
Topics: Antineoplastic Agents, Phytogenic; Drug Carriers; Drug Delivery Systems; Drug Development; Humans; Molecular Structure; Nanoparticles; Paclitaxel; Polymers
PubMed: 32682385
DOI: 10.2174/1871520620666200719001038 -
Advanced Science (Weinheim,... Feb 2024Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic...
Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti-cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient-derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.
Topics: Humans; Cell Line, Tumor; Paclitaxel; Phosphorylation; Signal Transduction; Triple Negative Breast Neoplasms; Elongation Factor 2 Kinase
PubMed: 38084501
DOI: 10.1002/advs.202305035 -
ACS Nano Sep 2022Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG =...
Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG = poly(ethylene glycol)) paclitaxel prodrugs by utilizing azobenzene (Azo) as a cleavable linker. The as-fabricated prodrugs could self-assemble into stable nanoparticles (PAP NPs) with high drug content ranging from 26 to 44 wt %. The Azo group in PAP NPs could be cleaved at the tumorous hypoxia microenvironment and promoted the release of paclitaxel for exerting cytotoxicity toward cancer cells. In addition, comparative researches revealed that the PAP NPs with the shorter methoxy-PEG chain (molecular weight = 750) possessed enhanced tumor suppression efficacy and alleviated off-target toxicity. Our work demonstrates a promising tactic to develop smart and simple nanomaterials for disease treatment.
Topics: Cell Line, Tumor; Humans; Hypoxia; Nanoparticles; Paclitaxel; Polyethylene Glycols; Prodrugs
PubMed: 36112532
DOI: 10.1021/acsnano.2c05341 -
Molecular Biology Reports May 2022In this study, the optimized niosomal formulation containing paclitaxel using non-ionic surfactants and cholesterol was designed and its cytotoxic effects against...
BACKGROUND
In this study, the optimized niosomal formulation containing paclitaxel using non-ionic surfactants and cholesterol was designed and its cytotoxic effects against different breast cancer cell lines and apoptosis gene expression analysis were also investigated.
METHODS AND RESULTS
Due to enhancing equation variables, the Box-Behnken method has been applied. Lipid/drug molar ratio, the amounts of Span 60, and cholesterol were selected as the target for optimization. The particle size of niosome loaded paclitaxel and entrapment efficiency proportion have been considered in the role of dependent variables. Then the cytotoxic activity of the optimized formulation was evaluated using an MTT assay against different breast cancer cell lines including MCF-7, T-47D, SkBr3, and MDA-MB-231. The expression level of Bax and Bcl-2 apoptosis genes was determined by Real-Time PCR. In this study, the optimized niosomal formulation revealed that the synthesized niosomes had a spherical appearance and had an average size of 192.73 ± 5.50 nm so that the percentage of drug loading was 94.71 ± 1.56%. Moreover, this formulation showed a controlled and slowed release of paclitaxel at different pH (7.4, 6.5, and 5.4). The cytotoxicity results demonstrated that cell viability in all concentrations of niosome loaded paclitaxel had profound cytotoxic effects on all studied breast cancer cell lines compared to the free paclitaxel (p < 0.05). In addition, the expression of apoptosis genes was much higher than that of free paclitaxel indicating the susceptibility of cells to apoptosis.
CONCLUSIONS
As a result, niosomal formulations containing paclitaxel can be used as a new drug delivery system to increase cytotoxicity and treatment of breast cancer in the upcoming future.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cholesterol; Female; Gene Expression; Humans; Liposomes; MCF-7 Cells; Paclitaxel; Particle Size
PubMed: 35235156
DOI: 10.1007/s11033-022-07199-2 -
Frontiers in Immunology 2023Protein tyrosine phosphatase non-receptor type 1 (PTPN1), a member of the protein tyrosine phosphatase superfamily, has been identified as an oncogene and therapeutic...
BACKGROUND
Protein tyrosine phosphatase non-receptor type 1 (PTPN1), a member of the protein tyrosine phosphatase superfamily, has been identified as an oncogene and therapeutic target in various cancers. However, its precise role in determining the prognosis of human cancer and immunological responses remains elusive. This study investigated the relationship between PTPN1 expression and clinical outcomes, immune infiltration, and drug sensitivity in human cancers, which will improve understanding regarding its prognostic value and immunological role in pan-cancer.
METHODS
The PTPN1 expression profile was obtained from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia databases. Kaplan-Meier, univariate Cox regression, and time-dependent receiver operating characteristic curve analyses were utilized to clarify the relationship between PTPN1 expression and the prognosis of pan-cancer patients. The relationships between PTPN1 expression and the presence of tumor-infiltrated immune cells were analyzed using Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data and Tumor Immune Estimation Resource. The cell counting kit-8 (CCK-8) assay was performed to examine the effects of PTPN1 level on the sensitivity of breast cancer cells to paclitaxel. Immunohistochemistry and immunoblotting were used to investigate the relationship between PTPN1 expression, immune cell infiltration, and immune checkpoint gene expression in human breast cancer tissues and a mouse xenograft model.
RESULTS
The pan-cancer analysis revealed that PTPN1 was frequently up-regulated in various cancers. High PTPN1 expression was associated with poor prognosis in most cancers. Furthermore, PTPN1 expression correlated highly with the presence of tumor-infiltrating immune cells and the expression of immune checkpoint pathway marker genes in different cancers. Furthermore, PTPN1 significantly predicted the prognosis for patients undergoing immunotherapy. The results of the CCK-8 viability assay revealed that PTPN1 knockdown increased the sensitivity of MDA-MB-231 and MCF-7 cells to paclitaxel. Finally, our results demonstrated that PTPN1 was associated with immune infiltration and immune checkpoint gene expression in breast cancer.
CONCLUSION
PTPN1 was overexpressed in multiple cancer types and correlated with the clinical outcome and tumor immunity, suggesting it could be a valuable potential prognostic and immunological biomarker for pan-cancer.
Topics: Humans; Animals; Mice; Female; Breast Neoplasms; Prognosis; Oncogenes; Paclitaxel; Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatase, Non-Receptor Type 1
PubMed: 37936713
DOI: 10.3389/fimmu.2023.1232047 -
Molecules (Basel, Switzerland) Jan 2022Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield...
Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Bile Acids and Salts; Cell Line; Cell Survival; Colonic Neoplasms; Deoxycholic Acid; Humans; Leukemia; Mice; Paclitaxel
PubMed: 35056786
DOI: 10.3390/molecules27020471 -
Current Drug Delivery Aug 2022Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor...
INTRODUCTION
Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor targeting and limit the usual side effects of chemotherapy.
METHODS
In this research, we developed the amphiphilic Heparin-poloxamer P403 (HSP) nanogel that could load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel were assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its dual drug-loaded platform showed high stability and spherical morphology.
RESULTS
The drug release profile indicated fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@CUR@PTX compared to free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR.
CONCLUSION
HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Heparin; Humans; Nanogels; Nanoparticles; Paclitaxel; Poloxamer; Spectroscopy, Fourier Transform Infrared
PubMed: 35366771
DOI: 10.2174/1567201819666220401095923 -
Bulletin of Mathematical Biology Dec 2022Triple-negative breast cancer (TNBC) is a heterogenous disease that is defined by its lack of targetable receptors, thus limiting treatment options and resulting in...
Triple-negative breast cancer (TNBC) is a heterogenous disease that is defined by its lack of targetable receptors, thus limiting treatment options and resulting in higher rates of metastasis and recurrence. Combination chemotherapy treatments, which inhibit tumor cell proliferation and regeneration, are a major component of standard-of-care treatment of TNBC. In this manuscript, we build a coupled ordinary differential equation model of TNBC with compartments that represent tumor proliferation, necrosis, apoptosis, and immune response to computationally describe the biological tumor affect to a combination of chemotherapies, doxorubicin (DRB) and paclitaxel (PTX). This model is parameterized using longitudinal [F]-fluorothymidine positron emission tomography (FLT-PET) imaging data which allows for a noninvasive molecular imaging approach to quantify the tumor proliferation and tumor volume measurements for two murine models of TNBC. Animal models include a human cell line xenograft model, MDA-MB-231, and a syngeneic 4T1 mammary carcinoma model. The mathematical models are parameterized and the percent necrosis at the end time point is predicted and validated using histological hematoxylin and eosin (H&E) data. Global Sobol' sensitivity analysis is conducted to further understand the role each parameter plays in the model's goodness of fit to the data. In both the MDA-MB-231 and the 4T1 tumor models, the designed mathematical model can accurately describe both tumor volume changes and final necrosis volume. This can give insight into the ordering, dosing, and timing of DRB and PTX treatment. More importantly, this model can also give insight into future novel combinations of therapies and how the immune system plays a role in therapeutic response to TNBC, due to its calibration to two types of TNBC murine models.
Topics: Humans; Animals; Mice; Triple Negative Breast Neoplasms; Cell Line, Tumor; Mathematical Concepts; Models, Biological; Paclitaxel; Cell Proliferation; Drug Therapy, Combination; Necrosis; Apoptosis
PubMed: 36542180
DOI: 10.1007/s11538-022-01108-1