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Bioorganic Chemistry Mar 2019Docetaxel is one of the most effective anticancer drugs. However, the current formulation of docetaxel contains Tween 80 and ethanol as the solvent, which can cause...
Docetaxel is one of the most effective anticancer drugs. However, the current formulation of docetaxel contains Tween 80 and ethanol as the solvent, which can cause severe side effects. Consequently, the development of new type of formulation of docetaxel with high efficiency and low side effects is a very important issue. In this study, we explored the covalent linking of docetaxel and albumin via one organic linker. 6-Maleimidocaproic acid was applied to link the C2' hydroxyl group of docetaxel with the cysteine-34 of albumin to obtain 1:1 docetaxel-albumin conjugate. The synthesized conjugate can control the release of docetaxel in the bovine serum. Furthermore, in vitro cell cytotoxicity experiments indicated that the docetaxel-albumin conjugate have high activities for human prostate cancer cell line PC3 and human breast cancer cell line MCF-7. The present study provides a valuable strategy for further development of a new type of docetaxel-albumin prodrug.
Topics: Animals; Antineoplastic Agents; Cattle; Cell Proliferation; Docetaxel; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Molecular Structure; PC-3 Cells; Serum Albumin; Structure-Activity Relationship
PubMed: 30366315
DOI: 10.1016/j.bioorg.2018.10.032 -
Current Medical Research and Opinion Aug 2021Docetaxel is a widely prescribed chemotherapy drug in oncology and post expiry of its patent, the drug has been marketed as a generic by multiple manufacturers. It is...
Docetaxel is a widely prescribed chemotherapy drug in oncology and post expiry of its patent, the drug has been marketed as a generic by multiple manufacturers. It is also classified as a narrow therapeutic window drug. Through enhanced permeability and retention effect, polymeric micelles can passively target agents to tumor tissue, thereby decreasing toxicity of the drug in normal tissue. However, various studies have raised concerns that generic docetaxel leads to greater incidences of toxicities among patients with cancer. Thus, we herein review the pharmaceutical challenges associated with different docetaxel formulations and provide insights into the dissimilarities in the quality and safety of branded and generic docetaxel formulations. Literature review reported that 90% of the generic formulations of docetaxel contain inadequate quantity of active drug and high levels of impurities. Higher amounts of solvents such as polysorbate 80 and ethanol in docetaxel formulation lead to severe toxicities such as febrile neutropenia, hematological, and cutaneous toxicities. In most of the studies, even minor changes in excipients, solvents, unbound fraction of docetaxel were associated with adverse events, while in few, the source of docetaxel remained unidentified. One study reported incidence of febrile neutropenia due to a switch in the formulation from branded to generic. The quality, safety, and efficacy of medicines will directly affect the life of patients, and therefore, use of docetaxel formulations that guarantee safety of patients are the necessity of the hour. Being an injectable anti-cancer drug, it is important to determine the consistency of the various formulations of docetaxel globally, conduct bioequivalence studies as per the regulatory standards, taking into account the permissible limits of the excipients or the presence of such unapproved excipients.
Topics: Antineoplastic Agents; Docetaxel; Drugs, Generic; Excipients; Humans; Therapeutic Equivalency
PubMed: 33998944
DOI: 10.1080/03007995.2021.1929895 -
International Journal of Cancer Aug 2023KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1... (Randomized Controlled Trial)
Randomized Controlled Trial
KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Docetaxel; Lung Neoplasms
PubMed: 37141294
DOI: 10.1002/ijc.34532 -
Pharmacology Research & Perspectives Aug 2020Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was... (Comparative Study)
Comparative Study
Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was the most commonly observed and dose-limiting toxicity. This study combined preclinical and clinical data and investigated incidence, severity and cause of oral docetaxel-induced diarrhea. In this study, incidence and severity of diarrhea in patients were compared to exposure to orally administered docetaxel. Intestinal toxicity after oral or intraperitoneal administration of docetaxel was further explored in mice lacking Cyp3a and mice lacking both Cyp3a and P-glycoprotein. In patients, severity of diarrhea increased significantly with an increase in AUC and C (P = .035 and P = .025, respectively), but not with an increase in the orally administered dose (P = .11). Furthermore, incidence of grade 3/4 diarrhea after oral docetaxel administration was similar as reported after intravenous docetaxel administration. Intestinal toxicity in mice was only observed at high systemic exposure to docetaxel and was similar after oral and intraperitoneal administration of docetaxel. In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Intravenous; Administration, Oral; Adult; Aged; Animals; Antineoplastic Agents; Area Under Curve; Cytochrome P-450 CYP3A; Diarrhea; Docetaxel; Female; Humans; Incidence; Injections, Intraperitoneal; Male; Mice; Mice, Knockout; Middle Aged; Severity of Illness Index
PubMed: 32725720
DOI: 10.1002/prp2.633 -
Biochemical and Biophysical Research... May 2023Due to the limited effective therapies, resistance to docetaxel is ordinarily fatal and remains a critical clinical challenge.β2-adrenergic receptor(β2-AR)can promote...
PURPOSE
Due to the limited effective therapies, resistance to docetaxel is ordinarily fatal and remains a critical clinical challenge.β2-adrenergic receptor(β2-AR)can promote the metastasis and invasion of prostate cancer, but the role in chemotherapy-resistant prostate cancer remains unclear.
METHODS
By downloading the GEO database in NCBI, the expression of β2-AR in different prostate tissues was analyzed. We constructed docetaxel-resistant prostate cancer cell lines by the method of dose-escalation. LC3B-labeled stable cells and shAtg5 knockdown stable cells were constructed by lentivirus infection. The molecular mechanism of β2-AR affecting docetaxel sensitivity through apoptosis and autophage were investigated by flow cytometry, mitochondrial membrane potential and western blot. Then we detected the interaction between autophagy and apoptotic by performing immunoprecipitation assay.
RESULTS
We show that restraining the activity of β-AR sensitized the cell response and reduced the resistance to docetaxel. The mechanism involves the regulation of β-AR in the cellular response to docetaxel through apoptosis and autophagy via caspase signaling and Atg5/AMPK/mTOR pathway as well as the effect of β-AR on the crosstalk between apoptosis and autophagy via p38 MAPK and JNK/c-Jun/FOXO3a signaling pathways.
CONCLUSION
Our data demonstrate that β-AR inhibitor-induced autophagy and apoptosis contribute to the effectiveness responses to docetaxel in castration-resistant prostate cancer, and in combination with pharmacological agents of β-AR and autophagy inhibitors may provide a potential therapeutic strategy to enhance the limited capacity of docetaxel to control castration-resistant prostate cancer.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Drug Resistance, Neoplasm; Cell Line, Tumor; Apoptosis; Receptors, Adrenergic; Receptors, Androgen
PubMed: 36989842
DOI: 10.1016/j.bbrc.2023.03.046 -
Iranian Journal of Medical Sciences Sep 2023Autophagy is a conservative mechanism for cell survival as the main response of cells to stress conditions. The present study aimed to assess the effect of docetaxel on...
BACKGROUND
Autophagy is a conservative mechanism for cell survival as the main response of cells to stress conditions. The present study aimed to assess the effect of docetaxel on the survival, fertilization, and expression of autophagy-related genes in vitrified oocytes.
METHODS
The study was conducted in 2018 at the Stem Cells Technology Research Center, Shiraz University of Medical Sciences (Shiraz, Iran). Denuded oocytes were randomly selected and assigned to five groups, namely control (n=133), docetaxel (n=136), docetaxel+cryoprotectants (n=146), docetaxel+vitrification (n=138), and vitrification (n=145). The effect of vitrification on the expression of autophagy-related gene 5 () and was determined using a real-time polymerase chain reaction. Data were analyzed using SPSS software (version 26.0) and GraphPad Prism 9.
RESULTS
Survival and fertilization rates in each experimental group were significantly reduced compared to the control group (P=0.001). After fertilization of oocytes, the 2-cell formation rate was significantly reduced in the docetaxel+vitrification and vitrification groups compared to the control and docetaxel groups (P=0.001 and P=0.001, respectively). Pre-incubation of oocytes with docetaxel reduced gene expression levels of and in the docetaxel+cryoprotectants and docetaxel+vitrification groups (P=0.001 and P=0.019, respectively). The expression level of these genes was also reduced in the docetaxel group compared to the control group (P=0.001).
CONCLUSION
Incubation of mouse metaphase II oocytes with docetaxel prior to vitrification reduced the expression of autophagy-related genes and increased survival and fertilization rates compared to untreated oocytes.
Topics: Mice; Animals; Vitrification; Docetaxel; Cryopreservation; Metaphase; Beclin-1; Oocytes; Cryoprotective Agents; Autophagy
PubMed: 37786462
DOI: 10.30476/IJMS.2023.88390.2811 -
Colloids and Surfaces. B, Biointerfaces Jul 2020Co-delivery of anti-tumor agents with outstanding stimulus-triggered drug release in tumor cells, especially with the aid of nanotechnology, provided the possibility to...
Co-delivery of anti-tumor agents with outstanding stimulus-triggered drug release in tumor cells, especially with the aid of nanotechnology, provided the possibility to enhance delivery efficiency for targeting tumor cells and antitumor efficacy. In this paper, docetaxel-dihydroartemisinin nanoconjugates linked by disulfide bond were designed to increase co-delivery and anti-tumor efficacy. Docetaxel and dihydroartemisinin were synthesized using two-step reaction and furtherly assembled to nanoconjugates. Nanoprescription was optimized to evaluate its physicochemical properties. In vitro anti-tumor activities of nanoformulation were assessed by MTT. The flow cytometry was adopted to analyze cell apoptosis and cell cycle arrest. The wound healing assay was used to evaluate antimigratory-property. In vivo pharmacokinetic and pharmacodynamic studies were investigated in rats and 4T1 bearing Balb/c mice model after intravenous injection, respectively. The chemical structure of conjugate was confirmed. The prepared nanoparticles possessed uniform size distribution (172.10 ± 1.70 nm, PDI 0.05 ± 0.01), was stable during storage period, sustained release profiles and sensitive reduction responsiveness. MTT assay indicated that the toxicity of nanoconjugates was slightly weak. Flow cytometry studies showed that nanoconjugates could promote early apoptosis significantly and mainly arose from G/G phase. The wound healing assay provided an obvious antimetastatic potential of nanoparticles in 4T1 cells. The result of pharmacokinetic study suggested that nanoconjugates exhibited higher exposure levels. In vivo pharmacodynamic research showed that mice treated with docetaxel-dihydroartemisinin nanoconjugates had lower systemic toxicity and higher survival ratio than those of control groups. This potential of nanoconjugates was developed as a novel nanoplateform to treat tumor.
Topics: Animals; Antineoplastic Agents; Apoptosis; Artemisinins; Cell Proliferation; Cell Survival; Disulfides; Docetaxel; Drug Screening Assays, Antitumor; Female; Injections, Subcutaneous; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Nanoparticles; Particle Size; Rats; Rats, Sprague-Dawley; Surface Properties; Tumor Cells, Cultured
PubMed: 32304917
DOI: 10.1016/j.colsurfb.2020.111018 -
Oncology Research and Treatment 2020
Review
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Thiohydantoins
PubMed: 32434198
DOI: 10.1159/000507054 -
International Journal of Molecular... Sep 2023Docetaxel is a first-line chemotherapy drug used to treat advanced prostate cancer, but patients who have used it often face the challenges of drug resistance and side...
Docetaxel is a first-line chemotherapy drug used to treat advanced prostate cancer, but patients who have used it often face the challenges of drug resistance and side effects. Kaempferol is a naturally occurring flavonol; our previous studies have confirmed that it has excellent anti-prostate activity. To investigate the anti-prostate cancer effects of docetaxel in combination with kaempferol, we conducted experiments at the cellular and whole-animal level. Plate cloning assays showed that the combination of docetaxel and kaempferol had a synergistic effect in inhibiting the proliferation of prostate cancer cells. The combination of these two compounds was found to induce autophagy in prostate cancer cells via transmission electron microscopy, and changes in the expression of autophagy-related proteins via Western blot assays also confirmed the occurrence of autophagy at the molecular level. We also confirmed the anti-prostate cancer effect of docetaxel in combination with kaempferol in vivo by establishing a mouse xenograft prostate cancer model. Autophagy-related proteins were also examined in mouse tumor tissues and verified the presence of autophagy in mouse tumor tissues. The above cellular and animal data suggest that docetaxel in combination with kaempferol has significant anti-prostate cancer effects and that it works by inducing autophagy in cells.
Topics: Male; Humans; Animals; Mice; Docetaxel; Kaempferols; Taxoids; Prostatic Neoplasms; Autophagy; Autophagy-Related Proteins; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis
PubMed: 37833967
DOI: 10.3390/ijms241914519 -
Cancer Letters Feb 2023Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence...
Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.
Topics: Male; Humans; Docetaxel; Proto-Oncogene Proteins c-akt; Prostate; Cell Line, Tumor; Neoplasm Recurrence, Local; Prostatic Neoplasms; Autophagy; Apoptosis; Cell Proliferation
PubMed: 36442771
DOI: 10.1016/j.canlet.2022.216011