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Medicinal Research Reviews Mar 2016Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a... (Review)
Review
Microtubules, tirelessly animated and highly dynamic structures, are vital for most cellular processes and their intricacies are still being revealed even after a century since their discovery. The importance of microtubules as chemotherapeutic targets cannot be overstated, and their clinical role is unlikely to abate in the near future. Indeed, improved understanding of microtubule biology could herald a new epoch of anticancer drug design by permitting fine-tuning of microtubule-targeting agents, the clinical utility of which is presently often limited by primary or acquired resistance. Paclitaxel, one such agent belonging to the taxane family, has proven a resoundingly successful treatment for many cancer patients; however, for too many others with paclitaxel-refractory tumors, the drug has offered nothing but side effects. Accumulating evidence suggests that microtubule-binding proteins (MBPs) can regulate paclitaxel sensitivity in a wide range of cancer types. Improved understanding of how these proteins can be assayed to predict treatment responses or manipulated pharmacologically to improve clinical outcomes could transform modern chemotherapy and is urgently awaited.
Topics: Biomarkers, Tumor; Drug Resistance, Neoplasm; Humans; Microtubule Proteins; Neoplasms; Paclitaxel; Precision Medicine
PubMed: 26332739
DOI: 10.1002/med.21378 -
International Journal of Molecular... Jul 2023Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian carcinoma that responds poorly to chemotherapy. Glutathione (GSH) is a primary antioxidant,...
Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian carcinoma that responds poorly to chemotherapy. Glutathione (GSH) is a primary antioxidant, which protects cells against reactive oxygen species (ROS). High levels of GSH are related to chemotherapeutic resistance. The glutamine/cystine transporter xCT is essential for intracellular GSH synthesis. However, whether xCT inhibition can overcome the resistance to chemotherapeutic agents in OCCC remains unclear. This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS. Moreover, combined treatment with PTX and SAS induced ferroptosis in the cells with low expression of glutathione peroxidase (GPx4), high levels of intracellular iron and significant lipid ROS accumulation. Therefore, our findings provide valuable information that the xCT inhibitor might be a promising therapeutic target for drug-resistant OCCC. The strategy of combined administration of PTX and SAS can potentially be used to treat OCCC and help to develop novel therapeutic methods.
Topics: Humans; Paclitaxel; Reactive Oxygen Species; Cell Line, Tumor; Cell Death; Sulfasalazine; Glutathione; Carcinoma
PubMed: 37511540
DOI: 10.3390/ijms241411781 -
Oncology (Williston Park, N.Y.) Aug 2018The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the...
The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials, as well as ongoing trials for which only preliminary results have been published, have fueled debates on the optimal dose and schedule; these have focused not only on weekly vs q3-weeks paclitaxel, but also on other modifications and the advisability of adding bevacizumab. Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Induction Chemotherapy; Ovarian Neoplasms; Paclitaxel
PubMed: 30153322
DOI: No ID Found -
Cardiovascular Engineering and... Jun 2018Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative... (Comparative Study)
Comparative Study
Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti-proliferative drugs, such as paclitaxel. Excipients thus play a vital role in the design and function of DCB, however methods to coat balloons with excipients and anti-proliferative drugs remain unknown. The goal of this study was to thus develop an approach to coat and evaluate DCB for various excipients. An air sprayer method was developed to deposit paclitaxel and various excipients onto non-coated commercially available angioplasty balloons. The coating of the angioplasty balloons was evaluated for drug deposition and coating efficiency using high performance liquid chromatography tandem mass spectrometry. Drug transfer and retention of the coated angioplasty balloons into arterial segments were evaluated ex vivo using harvested pig arteries in a pulsatile flow bioreactor. The air sprayer method successfully delivered varying excipients including bovine serum albumin (BSA), urea and iohexol. The air spray method was configured to coat four angioplasty balloons simultaneously with paclitaxel and iohexol with an average paclitaxel load of 4.0 ± 0.70 µg/mm. The intra-day (within) and inter-day (between) coating precisions, defined as relative standard deviation (RSD), was 17.2 and 15.5%, respectively. Ex vivo deployment of iohexol-paclitaxel DCB yielded an arterial paclitaxel concentration of 123.4 ± 44.68 ng/mg (n = 3) at 1 h, 126.7 ± 25.27 ng/mg (n = 3) at 1 day, and 12.9 ± 12.88 ng/mg (n = 3) at 7 days. This work provides proof-of-concept of a quick, inexpensive approach to coat commercially available angioplasty balloons with paclitaxel and various excipients.
Topics: Angioplasty, Balloon; Animals; Bioreactors; Cardiovascular Agents; Carotid Arteries; Coated Materials, Biocompatible; Drug Liberation; Excipients; Iohexol; Materials Testing; Paclitaxel; Serum Albumin, Bovine; Surface Properties; Sus scrofa; Tissue Culture Techniques; Tissue Distribution; Urea; Vascular Access Devices
PubMed: 29497966
DOI: 10.1007/s13239-018-0346-1 -
Aging Feb 2022Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus... (Meta-Analysis)
Meta-Analysis
Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus three-week treatment) remain contradictory in many randomized controlled trials (RCTs). Here, we performed a comprehensive meta-analysis to measure the efficacy and toxicities of these two dosing regimens. Four databases were systematically retrieved. RCTs comparing two paclitaxel dosing regimens for advanced malignant tumors with assessable outcomes (e.g., overall survival (OS), progression-free survival (PFS), toxicities, response rates) were included. In total, 19 eligible RCTs involving 9 674 patients were included. Meta-analysis of pan-cancers revealed that weekly paclitaxel treatment was more beneficial regarding PFS compared to three-week paclitaxel treatment (hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.82-0.99, = 0.02). Nevertheless, there was no significant difference in terms of OS between the two dosing regimens (HR = 0.98, 95%CI = 0.91-1.06, = 0.62) or other tested subgroups. In terms of serious adverse events, grade 3 or 4 (G3/4) neutropenia, G3/4 febrile neutropenia, G3/4 arthritis, and G3/4 alopecia occurred less often under weekly paclitaxel treatment. In summary, Weekly paclitaxel treatment demonstrates better PFS and fewer chemotherapy-induced hematological and non-hematological toxicities compared to the three-week paclitaxel regimen.
Topics: Carcinoma; Humans; Paclitaxel; Progression-Free Survival
PubMed: 35218640
DOI: 10.18632/aging.203919 -
AAPS PharmSciTech Feb 2018Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to...
Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to SKOV-3 cells at a molar ratio of 1 to 1 and in PTX ➔ GEM sequence. Liposomes were explored as a carrier of PTX and GEM combination. We optimized the drug loading in liposomes varying the preparation method and co-encapsulated PTX and GEM in a single liposome preparation maintaining the maximum loading efficiency of each drug. However, drug release kinetics from the co-loaded liposomes (LpPG) was suboptimal because of the detrimental effect of PTX on GEM-release control. Instead, a mixture of LpP and LpG, which were separately optimized according to the desired release kinetics, achieved a greater cytotoxic effect than LpPG, due to the attenuation of GEM release relative to PTX. This study illustrates that co-encapsulation in a single carrier is not always desirable for the delivery of drug combinations, when the activity depends on the dosing sequence. These combinations may benefit from the mixed liposome approach, which offers greater flexibility in controlling the ratio and release kinetics of component drugs.
Topics: Cell Line, Tumor; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Paclitaxel; Gemcitabine
PubMed: 28971370
DOI: 10.1208/s12249-017-0877-z -
Canadian Journal of Gastroenterology &... 2022Gastric cancer is one of the most common malignant tumors in the world. Albumin paclitaxel (Nab-PTX) is a novel microtubule inhibitor with albumin as the carrier....
Albumin Paclitaxel Compared with 5-Penfluorouracil, Lobaplatin, and Albumin Paclitaxel Combined with 5-Penfluorouracil in the Treatment of Human Gastric Cancer Cell AGS Line Autophagy and Apoptosis.
BACKGROUND
Gastric cancer is one of the most common malignant tumors in the world. Albumin paclitaxel (Nab-PTX) is a novel microtubule inhibitor with albumin as the carrier. Several clinical trials are underway in gastric cancer, but the autophagy mechanism of Nab-PTX on gastric cancer is still unclear. The autophagy and apoptosis effects of Nab-PTX compared with 5-pentafluorouracil (5-Fu) and lobaplatin (LBP) in gastric cancer are also unclear.
OBJECTIVE
This article will compare the effects of Nab-PTX, 5-Fu, LBP, and albumin paclitaxel + 5-pentafluorouracil (Nab-PTX + 5-Fu) on AGS cells from the perspective of autophagy and apoptosis, which is to provide new ideas and experimental evidence for gastric cancer.
METHOD
(1) Experimental groups were control (Ctrl), Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu. (2) CCK-8 assay was used to reflect cell viability and proliferation. (3) The flow cytometry was used to perform the 24-hour apoptosis and cell cycle of each group. (4) Western blot assay was used to investigate autophagy signal proteins LC3I/LC3II, LC3II/LC3I, SQSTM1/p62, Beclin-1, Atg12, Atg5, p-mULK1, p-AMPK, p-mTOR, and apoptosis signal proteins Bax and Bcl-2.
RESULTS
Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu inhibited AGS cells' proliferation and arrested the cell cycle. At the same time, each group increased the apoptosis of AGS cells to various degrees (Nab-PTX + 5-Fu > Nab-PTX > 5-Fu > LBP, respectively). The experimental results showed that Nab-PTX and Nab-PTX + 5-Fu promoted autophagy and apoptosis of AGS cells. The comparison of Nab-PTX, 5-Fu, and LBP between groups revealed that 5-Fu inhibited autophagy and the expression of apoptosis protein Bax. In LBP, abnormal activation of autophagy downstream, blocking of autophagy flow, abnormal increase of ATG12, and increased expression of apoptosis protein Bax occurred. Further study found that the autophagy upstream mechanism is different.
CONCLUSION
Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu can inhibit cell proliferation, promote cell apoptosis, and induce the difference in autophagy expression. The autophagy difference of this antitumor drug may be related to its inducing apoptosis. Meanwhile, Nab-PTX has a better antitumor effect than 5-Fu and LBP in gastric cancer, and the combination of Nab-PTX + 5-Fu has more antitumor advantages.
Topics: Albumins; Apoptosis; Autophagy; Cell Line, Tumor; Cyclobutanes; Fluorouracil; Humans; Organoplatinum Compounds; Paclitaxel; Stomach Neoplasms; bcl-2-Associated X Protein
PubMed: 35719323
DOI: 10.1155/2022/6015877 -
Oncology (Williston Park, N.Y.) Jun 2002Several clinical trials have explored the efficacy of docetaxel (Taxotere) as primary chemotherapy for breast cancer. Docetaxel has been evaluated as single-agent... (Review)
Review
Several clinical trials have explored the efficacy of docetaxel (Taxotere) as primary chemotherapy for breast cancer. Docetaxel has been evaluated as single-agent therapy, sequentially as a single agent following anthracycline-containing regimens, and in combination with anthracyclines, cisplatin, and trastuzumab (Herceptin) in patients with high-risk early breast cancer. Two large, randomized phase III trials have demonstrated significant improvements in clinical and pathologic response rates with the sequential addition of docetaxel to an anthracycline-containing preoperative regimen. A trial conducted in the United Kingdom demonstrated that docetaxel sequential to CVAP (cyclophosphamide [Cytoxan, Neosar], vincristine, doxorubicin [Adriamycin], prednisolone) produced a higher overall clinical response rate (94% vs 66%, P = .001) and pathologic complete response rate (34% vs 18%) compared to additional cycles of CVAP as primary chemotherapy. This translated into a survival advantage for docetaxel-treated patients, whose 3-year disease-free and overall survival were significantly improved (97% vs 84%; 90% vs 77%, P = .03). The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-27 demonstrated that primary doxorubicin/cyclophosphamide followed by docetaxel significantly increased the clinical complete response (65% vs 40%, P < .001) and pathologic complete response rates (25.6% vs 13.7%, P < .001) and decreased the rate of positive axillary nodes (40.5% vs 48.5%, P = .01). Final analysis of NSABP B-27 may also potentially demonstrate improved disease-free and overall survivals. Additional phase II and phase III randomized trials have compared docetaxel/anthracycline combinations with standard anthracycline-based regimens. Preliminary results have shown that incorporation of docetaxel can improve the rate of breast preservation surgery and the overall clinical and pathologic complete response rates.
Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Clinical Trials as Topic; Docetaxel; Female; Humans; Paclitaxel; Taxoids
PubMed: 12108896
DOI: No ID Found -
PloS One 2020Paclitaxel is an effective natural-source chemotherapeutic agent commonly applied to treat a vast range of cancers. In vitro Corylus avellana culture has been reported...
Paclitaxel is an effective natural-source chemotherapeutic agent commonly applied to treat a vast range of cancers. In vitro Corylus avellana culture has been reported as a promising and inexpensive system for paclitaxel production. Fungal elicitors have been made known as the most efficient strategy for the biosynthesis induction of secondary metabolites in plant in vitro culture. In this research, C. avellana cell suspension culture (CSC) was exposed to cell extract (CE) and culture filtrate (CF) derived from Camarosporomyces flavigenus, either individually or combined treatment, in mid and late log phase. There is no report on the use of whole fungal elicitors (the combined treatment of CE and CF) for the elicitation of secondary metabolite biosynthesis in plant in vitro culture. The combined treatment of CE and CF significantly led to more paclitaxel biosynthesis and secretion than the individual use of them. Also, multivariate statistical approaches including stepwise regression (SR), ordinary least squares regression (OLSR), principal component regression (PCR) and partial least squares regression (PLSR) were used to model and predict paclitaxel biosynthesis and secretion. Based on value account for (VAF), root mean square error (RMSE), coefficient of determination (R2), mean absolute percentage error (MAPE) and relative percent difference (RPD) can be concluded that mentioned regression models effectively worked only for modeling and predicting extracellular paclitaxel portion in C. avellana cell culture.
Topics: Ascomycota; Cell Culture Techniques; Cells, Cultured; Chromatography, High Pressure Liquid; Corylus; Least-Squares Analysis; Models, Biological; Paclitaxel; Principal Component Analysis
PubMed: 32673365
DOI: 10.1371/journal.pone.0236191 -
Journal of Controlled Release :... Oct 2017Nanoparticles are used to deliver anticancer drugs to solid tumors. However, clinical development of nanoparticles is challenging because of their limitations in...
Nanoparticles are used to deliver anticancer drugs to solid tumors. However, clinical development of nanoparticles is challenging because of their limitations in physicochemical properties, such as low drug loading efficiency and poor circulation stability. Low drug loading not only causes technical difficulty in administration but also increases the amount of co-delivered carrier materials, imposing biological burdens to patients. Poor circulation stability causes loss of pharmacokinetics benefits of nanoparticles. To overcome these challenges, we developed an albumin-coated nanocrystal (NC) formulation of paclitaxel (PTX) with 90% drug loading and high serum stability. The NC was produced by inducing crystallization of PTX in aqueous medium, coating the surface with albumin, and removing extra non-drug ingredients. Among three types of NC produced with different crystallization conditions, NC crystallized in the medium containing Pluronic F-127 then coated with albumin ("Cim-F-alb") had the smallest size and the most native albumin, thus showing the most favorable cell interaction profiles (low uptake by J774A.1 macrophages and high uptake by SPARC B16F10 melanoma cells). Cim-F-alb remained more stable in undiluted serum than Abraxane, a commercial albumin-based PTX nanoparticle formulation, while maintaining comparable cytotoxicity to those of Abraxane and solvent-dissolved PTX. In a mouse model of B16F10 melanoma, Cim-F-alb showed higher antitumor efficacy than Abraxane at the same dose. This study demonstrates the feasibility and benefits of delivering an anticancer drug using a carrier-free nanoparticle formulation with good circulation stability.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line; Cell Line, Tumor; Male; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Paclitaxel; Serum Albumin; Tumor Burden
PubMed: 28049022
DOI: 10.1016/j.jconrel.2016.12.040