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Cellular & Molecular Biology Letters 2019Paclitaxel is a well-known anticancer agent with a unique mechanism of action. It is considered to be one of the most successful natural anticancer drugs available. This... (Review)
Review
Paclitaxel is a well-known anticancer agent with a unique mechanism of action. It is considered to be one of the most successful natural anticancer drugs available. This study summarizes the recent advances in our understanding of the sources, the anticancer mechanism, and the biosynthetic pathway of paclitaxel. With the advancement of biotechnology, improvements in endophytic fungal strains, and the use of recombination techniques and microbial fermentation engineering, the yield of extracted paclitaxel has increased significantly. Recently, paclitaxel has been found to play a large role in tumor immunity, and it has a great potential for use in many cancer treatments.
Topics: Animals; Antineoplastic Agents, Phytogenic; Biotechnology; Fermentation; Fungi; Humans; Immunotherapy; Neoplasms; Paclitaxel
PubMed: 31223315
DOI: 10.1186/s11658-019-0164-y -
Molecular Biology of the Cell Sep 2014Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung...
Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle Checkpoints; Humans; Neoplasms; Paclitaxel
PubMed: 25213191
DOI: 10.1091/mbc.E14-04-0916 -
Biomolecules Nov 2019Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several... (Review)
Review
Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Paclitaxel
PubMed: 31783552
DOI: 10.3390/biom9120789 -
Cancer Research Jan 2023Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast...
UNLABELLED
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.
SIGNIFICANCE
Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
Topics: Humans; Female; Inflammatory Breast Neoplasms; Breast Neoplasms; Cell Line, Tumor; Signal Transduction; Paclitaxel; Stem Cells; STAT3 Transcription Factor
PubMed: 36409824
DOI: 10.1158/0008-5472.CAN-22-0423 -
International Journal of Molecular... Aug 2017Taxol, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action... (Review)
Review
Taxol, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol emphasizes the research done in the Horwitz' laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol.
Topics: Animals; Antineoplastic Agents, Phytogenic; Binding Sites; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Microtubules; Paclitaxel; Protein Binding; Protein Isoforms; Protein Subunits; Structure-Activity Relationship; Tubulin Modulators
PubMed: 28792473
DOI: 10.3390/ijms18081733 -
Experimental Neurology Feb 2020Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor... (Review)
Review
Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.
Topics: Animals; Antineoplastic Agents, Phytogenic; Humans; Mice; Paclitaxel; Peripheral Nervous System Diseases; Rats; Rodentia
PubMed: 31758983
DOI: 10.1016/j.expneurol.2019.113121 -
Journal of Experimental & Clinical... Nov 2021Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased...
BACKGROUND
Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. Therefore, we examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC).
METHODS
The effects of ferroptosis inducers and PGRMC1 gene silencing/overexpression were tested on head and neck cancer (HNC) cell lines and mouse tumor xenograft models. The results were analyzed about cell viability, death, lipid ROS and iron production, mRNA/protein expression and interaction, and lipid assays.
RESULTS
PCC had more free fatty acids, lipid droplets, and fatty acid oxidation (FAO) than their parental cells. PCC was highly sensitive to inhibitors of system xc cystine/glutamate antiporter (xCT), such as erastin, sulfasalazine, and cyst(e)ine deprivation, but less sensitive to (1S,3R)-RSL3. PGRMC1 silencing in PCC reduced ferroptosis sensitivity by xCT inhibitors, and PGRMC1 overexpression in parental cells increased ferroptosis by xCT inhibitors. Lipid droplets were degraded along with autophagy induction and autophagosome formation by erastin treatment in PCC. Lipophagy was accompanied by increased tubulin detyrosination, which was increased by SIRT1 activation but decreased by SIRT1 inhibition. FAO and lipophagy were also promoted by the interaction between lipid droplets and mitochondria.
CONCLUSION
PGRMC1 expression increased FAO and ferroptosis sensitivity from in vivo mice experiments. Our data suggest that PGRMC1 promotes ferroptosis by xCT inhibition in PCC.
Topics: Animals; Antineoplastic Agents, Phytogenic; Autophagy; Cell Line, Tumor; Ferroptosis; Humans; Male; Membrane Proteins; Mice; Mice, Nude; Paclitaxel; Receptors, Progesterone; Transfection
PubMed: 34749765
DOI: 10.1186/s13046-021-02168-2 -
Science Translational Medicine May 2022Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti-programmed death 1 (α-PD1) or anti-programmed death ligand 1...
Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti-programmed death 1 (α-PD1) or anti-programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 and CD8 T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.
Topics: Albumins; Animals; Breast Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Female; Humans; Mice; Nanoparticles; Paclitaxel; Tumor Microenvironment
PubMed: 35507675
DOI: 10.1126/scitranslmed.abl3649 -
Blood Jun 2022Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing...
Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. Although several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage non-Hodgkin lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47 due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of the US Food and Drug Administration-approved anticancer small molecule compounds, we identified paclitaxel as a potentiator that promoted the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward NHL cells. A combination with paclitaxel dramatically enhanced the anticancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that was only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the antitumor activities of macrophages.
Topics: CD47 Antigen; Humans; Immunosuppression Therapy; Immunotherapy; Lymphoma; Macrophages; Neoplasms; Paclitaxel; Phagocytosis; Tumor Microenvironment
PubMed: 35134139
DOI: 10.1182/blood.2021013901 -
Pharmacogenomics May 2010The microtubule-stabilizing drug paclitaxel is a cytotoxic agent widely used for the treatment of a variety of tumor types. Since its introduction to the clinic,... (Review)
Review
The microtubule-stabilizing drug paclitaxel is a cytotoxic agent widely used for the treatment of a variety of tumor types. Since its introduction to the clinic, modifications to the administration schedule and treatments for hypersensitivity reactions and neutropenia have significantly improved paclitaxel therapy. On the other hand, severe neurotoxicity and lack of response are still clinical challenges. During the last decade a deeper knowledge of paclitaxel pharmacokinetics and pharmacodynamics has been achieved, together with an in-depth characterization of genes involved in its elimination and therapeutic response. Pharmacogenetic studies aimed at the identification of paclitaxel outcome biomarkers have been performed, however, further efforts will be required to successfully integrate these and future results to provide the basis for personalized paclitaxel therapy.
Topics: Clinical Trials as Topic; Humans; Microtubules; Neoplasms; Paclitaxel; Pharmacogenetics
PubMed: 20415548
DOI: 10.2217/pgs.10.32