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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 -
Cell Research Mar 2023Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with...
Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.
Topics: Humans; ATPases Associated with Diverse Cellular Activities; B7-H1 Antigen; Immunotherapy; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Mitophagy; Paclitaxel; Protein Kinases
PubMed: 36627348
DOI: 10.1038/s41422-022-00766-z -
Cell Death and Differentiation Feb 2022The F-box and WD-repeat-containing protein 2 (FBXW2) plays a crucial role as an E3 ligase in regulating tumorigenesis. However, the functions of FBXW2 in breast cancer...
The F-box and WD-repeat-containing protein 2 (FBXW2) plays a crucial role as an E3 ligase in regulating tumorigenesis. However, the functions of FBXW2 in breast cancer are still unknown. Here, we find that nuclear factor-kB (NF-κB) p65 is a new substrate of FBXW2. FBXW2 directly binds to p65, leading to its ubiquitination and degradation. Interestingly, p300 acetylation of p65 blocks FBXW2 induced p65 ubiquitination. FBXW2-p65 axis is a crucial regulator of SOX2-induced stemness in breast cancer. Moreover, FBXW2 inhibits breast tumor growth by regulating p65 degradation in vitro and in vivo. FBXW2 overexpression abrogates the effects of p65 on paclitaxel resistance in vitro and in vivo. Furthermore, FBXW2 induced p65 degradation is also confirmed in FBXW2-knockout mice. Our results identify FBXW2 as an important E3 ligase for p65 degradation, which provide insights into the tumor suppressor functions of FBXW2 in breast cancer.
Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; F-Box Proteins; Female; Humans; Mice; NF-kappa B; Paclitaxel; Transcription Factor RelA; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34465889
DOI: 10.1038/s41418-021-00862-4 -
Molecular Pharmaceutics May 2021Albumin is an appealing carrier in nanomedicine because of its unique features. First, it is the most abundant protein in plasma, endowing high biocompatibility,... (Review)
Review
Albumin is an appealing carrier in nanomedicine because of its unique features. First, it is the most abundant protein in plasma, endowing high biocompatibility, biodegradability, nonimmunogenicity, and safety for its clinical application. Second, albumin chemical structure and conformation allows interaction with many different drugs, potentially protecting them from elimination and metabolism , thus improving their pharmacokinetic properties. Finally, albumin can interact with receptors overexpressed in many diseased tissues and cells, providing a unique feature for active targeting of the disease site without the addition of specific ligands to the nanocarrier. For this reason, albumin, characterized by an extended serum half-life of around 19 days, has the potential of promoting half-life extension and targeted delivery of drugs. Therefore, this article focuses on the importance of albumin as a nanodrug delivery carrier for hydrophobic drugs, taking advantage of the passive as well as active targeting potential of this nanocarrier. Particular attention is paid to the breakthrough NAB-Technology, with emphasis on the advantages of Nab-Paclitaxel (Abraxane), compared to the solvent-based formulations of Paclitaxel, i.e., CrEL-paclitaxel (Taxol) in a clinical setting. Finally, the role of albumin in carrying anticancer compounds is depicted, with a particular focus on the albumin-based formulations that are currently undergoing clinical trials. The article sheds light on the power of an endogenous substance, such as albumin, as a drug delivery system, signifies the importance of the drug vehicle in drug performance in the biological systems, and highlights the possible future trends in the use of this drug delivery system.
Topics: Albumins; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Carriers; Half-Life; Humans; Hydrophobic and Hydrophilic Interactions; Nanoparticles; Neoplasms; Paclitaxel; Serum Albumin, Human
PubMed: 33787270
DOI: 10.1021/acs.molpharmaceut.1c00046 -
Annals of Oncology : Official Journal... Aug 2021In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.
BACKGROUND
In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC.
PATIENTS AND METHODS
Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint.
RESULTS
Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug.
CONCLUSION
Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Paclitaxel; Progression-Free Survival; Triple Negative Breast Neoplasms
PubMed: 34219000
DOI: 10.1016/j.annonc.2021.05.801 -
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 -
Molecules (Basel, Switzerland) Dec 2020Taxol, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol has... (Review)
Review
Taxol, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol has been used to treat over one million patients, making it one of the most widely employed antitumoral drugs. Taxol was the first microtubule targeting agent described in the literature, with its main mechanism of action consisting of the disruption of microtubule dynamics, thus inducing mitotic arrest and cell death. However, secondary mechanisms for achieving apoptosis have also been demonstrated. Despite its wide use, Taxol has certain disadvantages. The main challenges facing Taxol are the need to find an environmentally sustainable production method based on the use of microorganisms, increase its bioavailability without exerting adverse effects on the health of patients and minimize the resistance presented by a high percentage of cells treated with paclitaxel. This review details, in a succinct manner, the main aspects of this important drug, from its discovery to the present day. We highlight the main challenges that must be faced in the coming years, in order to increase the effectiveness of Taxol as an anticancer agent.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Drug Resistance, Neoplasm; Humans; M Phase Cell Cycle Checkpoints; Microtubules; Neoplasms; Paclitaxel; Taxus
PubMed: 33348838
DOI: 10.3390/molecules25245986 -
Journal of Thoracic Oncology : Official... Sep 2021We aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
We aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC.
METHODS
In this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m) on day 1 or nab-paclitaxel (100 mg/m) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis.
RESULTS
Between May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4-19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9-16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68-1.07). Median progression-free survival was 4.2 months (95% CI: 3.9-5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9-4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63-0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0-36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9-20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively).
CONCLUSIONS
Nab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.
Topics: Albumin-Bound Paclitaxel; Albumins; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Lung Neoplasms; Nanoparticles; Paclitaxel; Treatment Outcome
PubMed: 33915251
DOI: 10.1016/j.jtho.2021.03.027 -
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