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Journal of Cancer Research and Clinical... Nov 2023It is unknown how the cell cycle plays a role in breast cancer (BC). This study aimed to establish a clinically applicable predictive model to predict the therapeutic...
BACKGROUND
It is unknown how the cell cycle plays a role in breast cancer (BC). This study aimed to establish a clinically applicable predictive model to predict the therapeutic responses and overall survival in BC patients.
MATERIALS AND METHODS
Cell cycle-related genes (CCGs) were identified within the Cancer Genome Atlas cohort (n is equal to 1001) and the Gene Expression Omnibus cohort (n is equal to 3265). An analysis of univariate and multivariate Cox was then conducted to develop a nomogram based on CCGs. After validating the nomogram, risk cohort stratification was established and the predictive value was examined. Finally, immune cell infiltration and therapeutic responses were analysed.
RESULTS
Based on 15 CCGs, 4 prognostic predictors were identified and entered into the nomogram. According to the curves of calibration, the estimated and observed value of the nomogram is in optimal agreement. Subsequently, stratification into two risk cohorts showed that the predictive value, immune cell infiltration and overall survival were better among patients with low risk. Immune checkpoint expression in patients with BC at higher risk was downregulated. Furthermore, the results of the study revealed that doxorubicin, paclitaxel, docetaxel, cisplatin and vinorelbine all had higher IC50 values in patients with high-risk BC.
CONCLUSION
The nomogram based on CCG could assess tumour immune micro-environment regulation and therapeutic responses of immunotherapy in BC. Moreover, it may provide novel information on the control of immune micro-environment infiltration in BC and aid in the development of targeted immunotherapy.
PubMed: 37540256
DOI: 10.1007/s00432-023-05198-9 -
Frontiers in Veterinary Science 2023Canine mesothelioma is a rare malignant tumor that mostly affects body cavities, such as the pericardial and pleural cavities. Chemotherapy plays a crucial role in the...
INTRODUCTION
Canine mesothelioma is a rare malignant tumor that mostly affects body cavities, such as the pericardial and pleural cavities. Chemotherapy plays a crucial role in the treatment of canine mesotheliomas. We aimed to compare the antitumor effects of single-agent and combination chemotherapeutic agents on patient-derived primary cultures of canine pericardial mesothelioma established in this study. We planned to generate xenograft models for future studies.
MATERIAL AND METHODS
Effusion samples were collected from three dogs with histologically diagnosed pericardial mesothelioma and used for primary culture. Cultured cells were characterized by immunostaining for pan-cytokeratin AE1/AE3, vimentin, Wilms' tumor suppressor gene 1 (WT1), and cytokeratin 5 (CK5). To assess the tumorigenic properties of cells in the effusion and generate a xenograft model, the cell suspension was injected into a severe combined immunodeficient (SCID) mouse either subcutaneously (SC) or intraperitoneally (IP). Lastly, chemosensitivity of established primary cultures against four drugs, doxorubicin, vinorelbine, carboplatin, and gemcitabine, by single-agent treatment as well as combination treatment of carboplatin at a fixed concentration, either 10 or 100 μM, and gemcitabine at different concentrations ranging from 0-1000 μM was assessed by cell viability assay.
RESULTS
Primary cultures were successfully generated and characterized by dual positivity for AE1/AE3 and vimentin and positive staining for WT-1 and CK5, confirming the mesothelial origin of the cells. In the xenograft models, SC mouse developed a subcutaneous mass, whereas IP mouse developed multiple intraperitoneal nodules. The masses were histopathologically consistent with mesotheliomas. The chemosensitivity assay revealed that carboplatin had the highest anti-tumor effects among the four tested single-agent treatments. Furthermore, carboplatin at 100 μM combined with gemcitabine at clinically relevant doses demonstrated the augmented anti-tumor effects compared to single-agent treatment.
DISCUSSION AND CONCLUSION
Primary cultures and xenograft models generated in this study could be useful tools for and studies of canine mesothelioma. Carboplatin is a highly effective chemotherapeutic agent against canine mesothelioma when used as a sole agent and in combination with gemcitabine.
PubMed: 38026668
DOI: 10.3389/fvets.2023.1267359 -
The Journal of Gene Medicine Jan 2024Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered...
INTRODUCTION
Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC).
METHODS
Three sets of ccRCC cohorts, ICGC_RECA-EU (n = 91), GSE76207 (n = 32) and TCGA-KIRC (n = 607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups.
RESULTS
A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy.
CONCLUSION
We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.
Topics: Humans; Male; Carcinoma, Renal Cell; RNA, Long Noncoding; Prognosis; Apoptosis; Kidney Neoplasms
PubMed: 37897262
DOI: 10.1002/jgm.3608 -
Current Pharmaceutical Biotechnology Apr 2024Breast cancer remains a leading cause of cancer-related deaths among women, primarily attributed to the formidable challenge of multidrug resistance, often driven by the...
BACKGROUND
Breast cancer remains a leading cause of cancer-related deaths among women, primarily attributed to the formidable challenge of multidrug resistance, often driven by the overexpression of the ABCB1 gene.
OBJECTIVE
This study aimed to assess the synergistic effects of siRNA, doxorubicin, and vinorelbine on ABCB1 gene expression and cell viability in doxorubicin-resistant MCF-7/ADR breast cancer cells, with siRNA targeting ABCB1 to reduce its expression and doxorubicin/ vinorelbine to eradicate cancer cells.
METHODS
Our methodology involved culturing MCF-7 and MCF-7/ADR cells in standard cell culture conditions. The synthesized siRNA sequences transfected cells with siRNA at final concentrations of 10, 20, and 30 nM and assessed cell viability using the MTT assay was performed. Real-time PCR was employed to quantify ABCB1 mRNA expression levels.
RESULTS
Results indicated that MCF-7/ADR cells exhibited substantial resistance to vinorelbine and doxorubicin compared to MCF-7 cells, displaying resistance at 12.50 μM and 25.00 μM for vinorelbine and 6.25 μM and 25.00 μM for doxorubicin. Remarkably, siRNA treatment effectively reversed drug resistance in MCF-7/ADR cells across all concentrations of vinorelbine and doxorubicin tested. When combined, siRNA, doxorubicin, and vinorelbine yielded a significantly greater reduction in cell viability compared to individual drug treatments, particularly at a 20 μM siRNA concentration. This combination therapy also significantly suppressed ABCB1 gene expression by a factor of 41.48 in MCF-7 cells relative to MCF-7/ADR cells.
CONCLUSION
these findings suggest that combining siRNA, doxorubicin, and vinorelbine holds promise as a therapeutic strategy to overcome ABCB1-mediated multidrug resistance in breast cancer. Further investigations and clinical trials are warranted to evaluate its clinical efficacy rigorously.
PubMed: 38616741
DOI: 10.2174/0113892010284774240328144105 -
International Journal of Molecular... Jun 2024Paclitaxel induces multipolar spindles at clinically relevant doses but does not substantially increase mitotic indices. Paclitaxel's anti-cancer effects are... (Review)
Review
Suppressing Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 Activity to Enhance the Effectiveness of Anti-Cancer Drugs That Induce Multipolar Mitotic Spindles.
Paclitaxel induces multipolar spindles at clinically relevant doses but does not substantially increase mitotic indices. Paclitaxel's anti-cancer effects are hypothesized to occur by promoting chromosome mis-segregation on multipolar spindles leading to apoptosis, necrosis and cyclic-GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) pathway activation in daughter cells, leading to secretion of type I interferon (IFN) and immunogenic cell death. Eribulin and vinorelbine have also been reported to cause increases in multipolar spindles in cancer cells. Recently, suppression of Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20) activity using CRISPR/Cas9 mutagenesis has been reported to increase sensitivity to Kinesin Family 18a (KIF18a) inhibition, which functions to suppress multipolar mitotic spindles in cancer cells. We propose that a way to enhance the effectiveness of anti-cancer agents that increase multipolar spindles is by suppressing the APC/C-CDC20 to delay, but not block, anaphase entry. Delaying anaphase entry in genomically unstable cells may enhance multipolar spindle-induced cell death. In genomically stable healthy human cells, delayed anaphase entry may suppress the level of multipolar spindles induced by anti-cancer drugs and lower mitotic cytotoxicity. We outline specific combinations of molecules to investigate that may achieve the goal of enhancing the effectiveness of anti-cancer agents.
Topics: Humans; Anaphase-Promoting Complex-Cyclosome; Antineoplastic Agents; Spindle Apparatus; Cdc20 Proteins; Neoplasms; Mitosis
PubMed: 38928036
DOI: 10.3390/ijms25126329 -
Cancers Jan 2024Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose...
Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose cisplatin represents an option for elderly. Outcomes (1) in elderly (≥70 years, = 158) vs. younger patients ( = 188) and (2), independently of age, in definitive radiochemotherapy, with low-dose cisplatin ( = 125) vs. cisplatin/vinorelbine ( = 76) were studied. Elderly included more males, had a lower Karnofsky index, more comorbidities, and lower stages. Low-dose cisplatin patients (vs. cisplatin/vinorelbine) had higher age, more comorbidities, and lower stages. We observed reduced dermatitis and dysphagia and increased anemia and thrombocytopenia in elderly vs. younger patients, without increased ≥grade 3 toxicities. Low-dose cisplatin was less toxic than cisplatin/vinorelbine. Survival outcomes were lower in elderly vs. younger and comparable between low-dose cisplatin and cisplatin/vinorelbine. In elderly, gender, Karnofsky index, stage, and multimodal treatment (including additional surgery/systemic therapy) were identified as prognostic factors. In conclusion, we found evidence for an acceptable toxicity profile and the need for improvement of outcomes in elderly with localized NSCLC. Multimodal strategies (including additional surgery/systemic treatment) showed favorable outcomes and should be reasonably considered in elderly who are deemed fit enough. Low-dose cisplatin should be discussed on an individual basis due to favorable toxicity and outcomes.
PubMed: 38254817
DOI: 10.3390/cancers16020327 -
Case Reports in Oncology 2024Capecitabine has rarely been associated with neurotoxicity. Cerebellar ataxia, multifocal leukoencephalopathy, and sensorimotor peripheral neuropathy have been reported...
INTRODUCTION
Capecitabine has rarely been associated with neurotoxicity. Cerebellar ataxia, multifocal leukoencephalopathy, and sensorimotor peripheral neuropathy have been reported in the literature. A case of 6th nerve palsy associated with capecitabine has also been described. This article reports the first case of capecitabine-related 4th nerve palsy.
CASE PRESENTATION
A 72-year-old Caucasian woman was referred by the Oncology Department because she had been complaining of binocular diplopia for 6 months. The symptoms started 1 month after the introduction of capecitabine. A diagnosis of right 4th nerve palsy was made using the Parks three-step test and the Hess test. Neuroimaging analysis was negative. A slow but progressive deterioration of function was confirmed during a year of follow-up. On suspicion of a chemotherapy-related palsy, capecitabine was discontinued and switched to vinorelbine. Subsequent improvement of the clinical picture was confirmed within 2 months.
CONCLUSION
The recognition of chemotherapy-related neurotoxicity is of paramount importance in the management of oncology patients. Once secondary invasion of the brain or the orbit by the tumor itself is ruled out, it must be suspected to prevent further deterioration.
PubMed: 38567168
DOI: 10.1159/000535349 -
Anticancer Research Mar 2024Evidence supports that use of aripiprazole sensitizes drug-resistant oral cancer cells. The aim of the study was to investigate whether aripiprazole can achieve...
BACKGROUND/AIM
Evidence supports that use of aripiprazole sensitizes drug-resistant oral cancer cells. The aim of the study was to investigate whether aripiprazole can achieve sensitization of highly drug-resistant breast cancer cells, as well as identify its relevant mechanisms of action.
MATERIALS AND METHODS
MCF-7/ADR, KB, and KBV20C breast cancer cells were treated with aripiprazole, vincristine (VIC), vinorelbine, vinblastine and their combination. Cell viability assay, annexin V analyses, cellular morphology and density observation with a microscope, western-blotting, fluorescence-activated cell sorting (FACS), and analysis for P-gp inhibitory activity were performed to investigate the drugs' mechanism of action.
RESULTS
We found that high drug resistance in MCF-7/ADR cells results from high P-gp inhibitory activity via overexpression of P-gp. Aripiprazole reduced cell viability, increased G arrest, and upregulated apoptosis when used as a co-treatment with VIC. Furthermore, we demonstrated that co-treatment with vinorelbine and vinblastine increased the sensitization of MCF-7/ADR breast cancer cells to aripiprazole. We confirmed that VIC-aripiprazole combination has much higher sensitization effects than either VIC-thioridazine or VIC-trifluoperazine co-treatment in MCF-7/ADR cells, since the previously known bipolar drugs (thioridazine and trifluoperazine) has lower P-gp inhibitory activity. However, aripiprazole-induced sensitization was not observed in VIC-treated MDA-MB-231 breast cancer cells suggesting that combination therapy with aripiprazole is specific for P-gp-overexpressing drug-resistant breast cancer cells.
CONCLUSION
Co-treatment with low doses of aripiprazole sensitized MCF-7/ADR cells to VIC. Combination therapy with aripiprazole may be a valuable tool for delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant breast cancer cells.
Topics: Humans; Female; Vincristine; ATP Binding Cassette Transporter, Subfamily B, Member 1; Aripiprazole; Vinorelbine; Breast Neoplasms; Vinblastine; MCF-7 Cells; Thioridazine; Trifluoperazine; Drug Resistance, Neoplasm; Cell Line, Tumor; ATP Binding Cassette Transporter, Subfamily B; Doxorubicin
PubMed: 38423668
DOI: 10.21873/anticanres.16900 -
Bioinformation 2023The atomic resolution model of US9, UL20, and gH protein of HSV is known. Hence, the ligand protein interaction of the US9, UL20, and gH protein models were carried out...
The atomic resolution model of US9, UL20, and gH protein of HSV is known. Hence, the ligand protein interaction of the US9, UL20, and gH protein models were carried out with synthetic drugs like acyclovir, bexarotene, vinorelbine, foscarnet, famciclovir, cidofovir and two plant derived natural drug acacetin and anthraquinone. Based on structure and docking study, it is predicted that protein US20 and gH binds with particular anti-HSV drug i.e. acyclovir, cidofovir, acacetin and famciclovir, acacetin respectively, while interaction of different protein is different with drugs.
PubMed: 37928488
DOI: 10.6026/97320630019981 -
Fundamental & Clinical Pharmacology Feb 2024There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as...
Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model.
BACKGROUND
There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet.
OBJECTIVES
Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms.
METHODS
Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion.
RESULTS
The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis.
CONCLUSION
This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.
Topics: Animals; Mice; Vinorelbine; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Vinblastine; Melanoma; Cisplatin; Antineoplastic Agents; Drug Therapy, Combination; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37458143
DOI: 10.1111/fcp.12939