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Advanced Science (Weinheim,... Feb 2024Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic...
Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti-cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient-derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.
Topics: Humans; Cell Line, Tumor; Paclitaxel; Phosphorylation; Signal Transduction; Triple Negative Breast Neoplasms; Elongation Factor 2 Kinase
PubMed: 38084501
DOI: 10.1002/advs.202305035 -
Scientific Reports Jun 2023There is substantial evidence that albumin-bound paclitaxel (nab-paclitaxel) is effective and safe for the treatment of breast, lung and pancreatic cancers. However, it...
There is substantial evidence that albumin-bound paclitaxel (nab-paclitaxel) is effective and safe for the treatment of breast, lung and pancreatic cancers. However, it can still cause adverse effects by affecting cardiac enzymes, hepatic enzyme metabolism and blood routine related indicators, which affects the use of chemotherapy for a full course of treatment. However, there are no relevant clinical studies to systematically observe the effects and dynamics of albumin-bound paclitaxel on cardiac enzymes, liver enzyme metabolism, and routine blood-related indices. The purpose of our study was to determine the levels of serum creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), white blood cells (WBC) and hemoglobin (HGB) in cancer patients treated with albumin-conjugated paclitaxel. This study retrospectively analyzed 113 patients with cancer. Patients who had received two cycles of nab-paclitaxel 260 mg/m (administered intravenously on days 1, 8, and 15 of each 28-day cycle) were selected. Serum Cre, AST, ALT, LDH, CK, and CK-MB activities, WBC counts, and HGB levels were measured before and after treatment with two cycles. Fourteen cancer types were analyzed. The distribution of cancer types in patients was mainly concentrated in lung, ovarian, and breast cancer. Nab-paclitaxel treatment markedly decreased Cre, AST, LDH, and CK activities in the serum and WBC counts and HGB levels, respectively. Serum Cre and CK activities and HGB levels were remarkably downregulated at baseline compared to healthy controls. Patients receiving nab-paclitaxel treatment cause metabolic disorders in tumor patients by reducing the decrease of Cre, AST, LDH, CK, CK-MB, WBC and HGB indexes, thus inducing the occurrence of cardiovascular events, hepatotoxic events and fatigue and other symptoms. Therefore, for tumor patients, although receiving nab-paclitaxel improves the anti-tumor effect, it is still necessary to closely monitor the changes of related enzymatic and routine blood indicators, so as to detect and intervene at an early stage.
Topics: Humans; Female; Albumin-Bound Paclitaxel; Retrospective Studies; Paclitaxel; Albumins; Breast Neoplasms; Creatine Kinase; Creatine Kinase, MB Form
PubMed: 37270638
DOI: 10.1038/s41598-023-35992-x -
International Journal of Nanomedicine 2020It is of great significance to develop intelligent co-delivery systems for cancer chemotherapy with improved therapeutic efficacy and few side-effects.
BACKGROUND
It is of great significance to develop intelligent co-delivery systems for cancer chemotherapy with improved therapeutic efficacy and few side-effects.
MATERIALS AND METHODS
Here, we reported a co-delivery system based on pH-sensitive polyprodrug micelles for simultaneous delivery of doxorubicin (DOX) and paclitaxel (PTX) as a combination chemotherapy with pH-triggered drug release profiles. The physicochemical properties, drug release profiles and mechanism, and cytotoxicity of PTX/DOX-PMs have been thoroughly investigated.
RESULTS AND DISCUSSION
The pH-sensitive polyprodrug was used as nanocarrier, and PTX was encapsulated into the micelles with high drug-loading content (25.6%). The critical micelle concentration (CMC) was about 3.16 mg/L, indicating the system could form the micelles at low concentration. The particle size of PTX/DOX-PMs was 110.5 nm, and increased to approximately 140 nm after incubation for 5 days which showed that the PTX/DOX-PMs had high serum stability. With decrease in pH value, the particle size first increased, and thenwas no longer detectable. Similar change trend was observed for CMC values. The zetapotential increased sharply with decrease in pH. These results demonstrated the pHsensitivity of PTX/DOX-PMs. In vitro drug release experiments and study on release mechanism showed that the drug release rate and accumulative release for PTX and DOX were dependent on the pH, showing the pH-triggered drug release profiles. Cytotoxicity assay displayed that the block copolymer showed negligible cytotoxicity, while the PTX/DOX-PMs possessed high cytotoxic effect against several tumor cell lines compared with free drugs and control.
CONCLUSION
All the results demonstrated that the co-delivery system based on pH-sensitive polyprodrug could be a potent nanomedicine for combination cancer chemotherapy. In addition, construction based on polyprodrug and chemical drug could be a useful method to prepare multifunctional nanomedicine.
Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Mice; Micelles; NIH 3T3 Cells; Neoplasms; Paclitaxel; Particle Size; Polymers; Prodrugs; Static Electricity
PubMed: 32494132
DOI: 10.2147/IJN.S249144 -
Frontiers in Immunology 2023Protein tyrosine phosphatase non-receptor type 1 (PTPN1), a member of the protein tyrosine phosphatase superfamily, has been identified as an oncogene and therapeutic...
BACKGROUND
Protein tyrosine phosphatase non-receptor type 1 (PTPN1), a member of the protein tyrosine phosphatase superfamily, has been identified as an oncogene and therapeutic target in various cancers. However, its precise role in determining the prognosis of human cancer and immunological responses remains elusive. This study investigated the relationship between PTPN1 expression and clinical outcomes, immune infiltration, and drug sensitivity in human cancers, which will improve understanding regarding its prognostic value and immunological role in pan-cancer.
METHODS
The PTPN1 expression profile was obtained from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia databases. Kaplan-Meier, univariate Cox regression, and time-dependent receiver operating characteristic curve analyses were utilized to clarify the relationship between PTPN1 expression and the prognosis of pan-cancer patients. The relationships between PTPN1 expression and the presence of tumor-infiltrated immune cells were analyzed using Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data and Tumor Immune Estimation Resource. The cell counting kit-8 (CCK-8) assay was performed to examine the effects of PTPN1 level on the sensitivity of breast cancer cells to paclitaxel. Immunohistochemistry and immunoblotting were used to investigate the relationship between PTPN1 expression, immune cell infiltration, and immune checkpoint gene expression in human breast cancer tissues and a mouse xenograft model.
RESULTS
The pan-cancer analysis revealed that PTPN1 was frequently up-regulated in various cancers. High PTPN1 expression was associated with poor prognosis in most cancers. Furthermore, PTPN1 expression correlated highly with the presence of tumor-infiltrating immune cells and the expression of immune checkpoint pathway marker genes in different cancers. Furthermore, PTPN1 significantly predicted the prognosis for patients undergoing immunotherapy. The results of the CCK-8 viability assay revealed that PTPN1 knockdown increased the sensitivity of MDA-MB-231 and MCF-7 cells to paclitaxel. Finally, our results demonstrated that PTPN1 was associated with immune infiltration and immune checkpoint gene expression in breast cancer.
CONCLUSION
PTPN1 was overexpressed in multiple cancer types and correlated with the clinical outcome and tumor immunity, suggesting it could be a valuable potential prognostic and immunological biomarker for pan-cancer.
Topics: Humans; Animals; Mice; Female; Breast Neoplasms; Prognosis; Oncogenes; Paclitaxel; Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatase, Non-Receptor Type 1
PubMed: 37936713
DOI: 10.3389/fimmu.2023.1232047 -
Molecules (Basel, Switzerland) Jan 2022Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield...
Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Bile Acids and Salts; Cell Line; Cell Survival; Colonic Neoplasms; Deoxycholic Acid; Humans; Leukemia; Mice; Paclitaxel
PubMed: 35056786
DOI: 10.3390/molecules27020471 -
Asian Pacific Journal of Cancer... Sep 2023Addressing both the initial treatment response and subsequent paclitaxel resistance is a pivotal concern. Nano drug delivery, an emerging approach, presents a...
OBJECTIVE
Addressing both the initial treatment response and subsequent paclitaxel resistance is a pivotal concern. Nano drug delivery, an emerging approach, presents a cutting-edge alternative to conventional chemotherapy.
METHODS
This investigation synthesized PEGylated nanoparticles (NPs) via the Reverse Phase Evaporation technique for liposomal NPs. Characteristics such as zeta potential, size, drug release and polydispersity index (PDI) were subjected to evaluation. Subsequently, cytotoxicity assays were conducted on gastric cancer cells (AGS) following 24 and 48-hour incubation periods.
RESULTS
In this study, the liposomal NPs had a zeta potential of -22 mV and a particle size of 285 nm. The Entrapment efficiency was determined as 41% that occurred physically. Additionally, the liposomal NPs demonstrated a high drug retention rate (39% remained after 72 hours), and they exhibited significantly increased cytotoxicity compared to the free drug, confirming their effectiveness as a suitable carrier for paclitaxel during both incubation periods (P<0.05).
CONCLUSION
These findings collectively advocate the potential of liposomal NPs as promising contenders for effective nano-drug application in propelling chemotherapy forward.
Topics: Humans; Stomach Neoplasms; Antineoplastic Agents; Paclitaxel; Liposomes; Nanoparticles; Particle Size; Drug Carriers
PubMed: 37774084
DOI: 10.31557/APJCP.2023.24.9.3291 -
International Journal of Molecular... Aug 2022Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the...
Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.
Topics: Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Glutamine; Humans; Mechanistic Target of Rapamycin Complex 1; Ovarian Neoplasms; Paclitaxel; Ribosomal Protein S6 Kinases; Signal Transduction
PubMed: 35955892
DOI: 10.3390/ijms23158761 -
Arteriosclerosis, Thrombosis, and... Dec 2023Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular...
BACKGROUND
Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation.
METHODS
Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing.
RESULTS
We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies.
CONCLUSIONS
We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli.
Topics: Humans; Mice; Animals; Endothelial Cells; Aorta; Sirolimus; Paclitaxel; Sequence Analysis, RNA; Stress, Mechanical; Cells, Cultured
PubMed: 37732484
DOI: 10.1161/ATVBAHA.123.319283 -
Cell Death & Disease Dec 2023Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic...
Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic agents. However, most TNBCs acquire resistance to chemotherapy, thereby lowering the therapeutic outcome. In addition to oncogenic mutations in TNBC, microenvironment-induced mechanisms render chemoresistance more complex and robust in vivo. Here, we aimed to analyze whether depletion of Munc18-1 interacting protein 3 (Mint3), which activates hypoxia-inducible factor 1 (HIF-1) during normoxia, sensitizes TNBC to chemotherapy. We found that Mint3 promotes the chemoresistance of TNBC in vivo. Mint3 depletion did not affect the sensitivity of human TNBC cell lines to doxorubicin and paclitaxel in vitro but sensitized tumors of these cells to chemotherapy in vivo. Transcriptome analyses revealed that the Mint3-HIF-1 axis enhanced heat shock protein 70 (HSP70) expression in tumors of TNBC cells. Administering an HSP70 inhibitor enhanced the antitumor activity of doxorubicin in TNBC tumors, similar to Mint3 depletion. Mint3 expression was also correlated with HSP70 expression in human TNBC specimens. Mechanistically, Mint3 depletion induces glycolytic maladaptation to the tumor microenvironment in TNBC tumors, resulting in energy stress. This energy stress by Mint3 depletion inactivated heat shock factor 1 (HSF-1), the master regulator of HSP expression, via the AMP-activated protein kinase/mechanistic target of the rapamycin pathway following attenuated HSP70 expression. In conclusion, Mint3 is a unique regulator of TNBC chemoresistance in vivo via metabolic adaptation to the tumor microenvironment, and a combination of Mint3 inhibition and chemotherapy may be a good strategy for TNBC treatment.
Topics: Humans; Carrier Proteins; Cell Line, Tumor; Doxorubicin; Paclitaxel; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 38081808
DOI: 10.1038/s41419-023-06352-4 -
BMC Cancer Jul 2021Although various clinical trials and real-life studies have tried to explore the value of nab-paclitaxel mono-chemotherapy for metastatic breast cancer (MBC), the safety... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although various clinical trials and real-life studies have tried to explore the value of nab-paclitaxel mono-chemotherapy for metastatic breast cancer (MBC), the safety and efficacy of nab-paclitaxel remain unclear which need to be systematically evaluated.
METHODS
Electronic searches for prospective clinical trials evaluating nab-paclitaxel monotherapy for MBC were performed. Requisite data were extracted, integrated and analysed from the included studies according to the different study designs using systematic review and meta-analysis. Meta-regression and subgroup analysis were further performed to explore the potential risk factors affecting each individual outcome of interest following nab-paclitaxel monotherapy.
RESULTS
Twenty-two studies with 3287 MBC patients were included. A total of 1685 MBC patients received nab-paclitaxel as first-line therapy, 640 patients as further-line therapy, and 962 patients as mixed-line therapy. A total of 1966 MBC patients (60.40%) received nab-paclitaxel weekly, 1190 patients (36.56%) received nab-paclitaxel triweekly and 99 patients (3.04%) received nab-paclitaxel biweekly. The overall incidence rates of all-grade neutropenia, leukopenia, peripheral sensory neuropathy, and fatigue were 52% (95% CI, 38-66%, I = 98.97%), 58% (95% CI, 43-73%, I = 97.72%), 58% (95% CI, 48-68%, I = 97.17%), and 49% (95% CI, 41-56%, I = 94.39%), respectively. The overall response rate (ORR) was 40% (95% CI, 35-45%, I = 98.97%), and the clinical benefit rate (CBR) was 66% (95% CI, 59-73%, I = 98.97%) following nab-paclitaxel monotherapy. The median progression-free survival (PFS) was 7.64 months (95% CI, 6.89-8.40 months, I = 92.3%), and the median overall survival (OS) was 24.51 months (95% CI, 21.25-27.78 months, I = 92.7%). Treatment line, human epidermal growth factor receptor-2(Her-2)-negative status and dosage were found to be sources of heterogeneity among the included studies. According to the meta-regression and subgroup analysis, grade 3/4 neutropenia occurred less frequently in Her-2-negative patients than in the entire population (P = 0.046). Patients who received first-line nab-paclitaxel monotherapy showed a higher ORR (P = 0.006) and longer PFS (P = 0.045). Efficacy outcomes were not affected by the administration schedule. However, within the same schedule, patients appeared to have a superior ORR (P = 0.044) and longer PFS (P = 0.03) with an increasing dosage of nab-paclitaxel administered.
CONCLUSIONS
The benefits brought by nab-paclitaxel mono-chemotherapy in the treatment of MBC are considerable while the harm is generally manageable. Further study and validation are needed to figure out the roles which the dosage, schedule and other factors play actually in nab-paclitaxel chemotherapy.
Topics: Albumins; Breast Neoplasms; Female; Humans; Neoplasm Metastasis; Paclitaxel; Risk Factors; Treatment Outcome
PubMed: 34275458
DOI: 10.1186/s12885-021-08441-z