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Bioinformation 2020Lipocalin 2 (Lcn2, also called as neutrophil gelatinase-associated lipocalin) is a member of the lipocalin family and a known target for breast cancer. Therefore, it is...
Lipocalin 2 (Lcn2, also called as neutrophil gelatinase-associated lipocalin) is a member of the lipocalin family and a known target for breast cancer. Therefore, it is of interest to use Docetaxel as a scaffold to design molecules with improved efficiency from naturally derived phytochemicals. We document 10 analogues (4Deacetyltaxol, 7Acetyltaxol, Cabazitaxel, Cephalomannine, Docetaxal, Deacetyltaxol, Docetaxeltrihydrate, Ortataxel, Paclitaxel, Taxoline) having optimal binding with Lipocalin 2 in comparison with Docetaxel. This data is highly useful for consideration in the design and development of drugs for breast cancer.
PubMed: 32884206
DOI: 10.6026/97320630016438 -
Cancer Letters Oct 2020Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study...
Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study was to screen new-generation taxanes for their efficiency against both PTX-sensitive and PTX-resistant breast cancer cells. From twelve compounds, difluorovinyl-ortataxel (DFV-OTX) displayed potent cytotoxic activities against both PTX-sensitive and PTX-resistant breast cancer cells. Moreover, DFV-OTX effectively induced tubulin/microtubule polymerization and G2/M phase arrest, leading to apoptosis in both PTX-sensitive and PTX-resistant cancer cells. Molecular docking analysis showed that DFV-OTX possesses unique hydrogen-bonding and van der Waals interactions with β-tubulin. LC-MS/MS analysis also demonstrated that the intracellular drug amount of DFV-OTX was lower than that of PTX, which would be critical to overcome PTX-resistance. Furthermore, DFV-OTX exhibited clear efficacy in the MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Taken together, our results demonstrate that the novel taxane, DFV-OTX, can effectively overcome PTX-resistance in MDA-MB-231R cells, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation and a distinct mode of action in MCF-7R cells. Our results strongly indicate that DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Female; G2 Phase Cell Cycle Checkpoints; Humans; Mice; Mice, Inbred BALB C; Paclitaxel; Taxoids; Tubulin
PubMed: 32730778
DOI: 10.1016/j.canlet.2020.06.025 -
Journal of Neuro-oncology May 2019Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment.
METHODS
In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints.
RESULTS
Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients.
CONCLUSION
Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time.
TRIAL REGISTRATION
This study is registered with ClinicalTrials.gov, number NCT01989884.
Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Survival Rate; Taxoids
PubMed: 30726533
DOI: 10.1007/s11060-019-03116-z