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Oncology Letters Aug 2024Skin metastasis from ovarian cancer is rare, and its prognosis is poor. Effective therapeutic strategies are currently lacking, but the combination of various treatment...
Skin metastasis from ovarian cancer is rare, and its prognosis is poor. Effective therapeutic strategies are currently lacking, but the combination of various treatment methods shrink the tumor and relieve symptoms. The present study reports a rare case of advanced ovarian cancer with skin metastases and intestinal wall thickening, along with a BRCA1 DNA repair associated (BRCA1) mutation. After standard first-line treatment and non-standard second-line treatment, the patient developed skin metastases. The patient's skin itching, pain and lesions were completely relieved after administering bevacizumab in combination with paclitaxel and carboplatin. After 4 months, skin metastases recurred along with anal distension during maintenance treatment with oral poly(ADP ribose) polymerase (PARP) inhibitors. The patient was treated again with bevacizumab combined with docetaxel, and the anal distension was significantly relieved. Angiogenesis therapy combined with chemotherapy is effective, but that the disease-free survival time is short, and PARP inhibitor maintenance effect is limited even in cases with a BRCA1 gene mutation.
PubMed: 38872856
DOI: 10.3892/ol.2024.14481 -
International Immunopharmacology Jun 2024The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways...
The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.
PubMed: 38870880
DOI: 10.1016/j.intimp.2024.112437 -
Integrative Cancer Therapies 2024Natural products are increasingly gaining interest as potential new drug candidates for cancer treatment. Herbal formula, which are combinations of several herbs, are... (Review)
Review
BACKGROUND
Natural products are increasingly gaining interest as potential new drug candidates for cancer treatment. Herbal formula, which are combinations of several herbs, are primarily used in East Asia and have a long history of use that continues today. Recently, research exploring the combination of herbal formulas and chemotherapy for cancer treatment has been on the rise.
METHODS
This study reviewed research on the co-administration of herbal formulas and chemotherapy for cancer treatment. The databases PubMed, Embase, and Cochrane Library were used for article searches. The following keywords were employed: "Antineoplastic agents," "Chemotherapy," "Phytotherapy," "Herbal medicine," "Drug synergism," and "Synergistic effect." The selection process focused on studies that investigated the synergistic interaction between herbal formulas and chemotherapeutic agents.
RESULTS
Among the 30 studies included, 25 herbal formulas and 7 chemotherapies were used. The chemotherapy agents co-administered included cisplatin, 5-fluorouracil, docetaxel, doxorubicin, oxaliplatin, irinotecan, and gemcitabine. The types of cancer most frequently studied were lung, breast, and colon cancers. Most studies evaluating the anticancer efficacy of combined herbal formula and chemotherapy treatment were conducted in vitro or in vivo.
DISCUSSION
Most studies reported synergistic effects on cytotoxicity, apoptosis, and tumor growth inhibition. These effects were found to be associated with cell cycle arrest, anti-angiogenesis, and gene expression regulation. Further studies leading to clinical trials are required. Clinical experiences in East Asian countries could provide insights for future research.
Topics: Humans; Drug Synergism; Neoplasms; Apoptosis; Phytotherapy; Antineoplastic Agents; Animals; Plants, Medicinal; Antineoplastic Combined Chemotherapy Protocols; Herbal Medicine
PubMed: 38867515
DOI: 10.1177/15347354241259416 -
Gastric Cancer : Official Journal of... Jun 2024
PubMed: 38867085
DOI: 10.1007/s10120-024-01519-0 -
Gastroenterology Jun 2024Patient-derived organoids (PDO) are promising tumor avatars that could enable ex vivo drug tests to personalize patients' treatment in the frame of functional precision...
BACKGROUND
Patient-derived organoids (PDO) are promising tumor avatars that could enable ex vivo drug tests to personalize patients' treatment in the frame of functional precision oncology (FPM). Yet, clinical evidence remain scarce. This study aims to evaluate whether PDO can be implemented in clinical practice to benefit patients with advanced refractory pancreatic adenocarcinoma (PDAC).
METHODS
During 2021-2022, 87 patients were prospectively enrolled in an IRB-approved protocol. Inclusion criteria were: histologically-confirmed PDAC, tumor site accessible. A panel of 25 approved antitumor therapies (chemogram) was tested and compared to patient responses to assess PDO predictive values and map the drug sensitivity landscape in PDAC.
RESULTS
Fifty-four PDOs were generated from 87 pretreated patients (take-on rate 62%). The main PDO mutations were KRAS (96%), TP53 (88%) and CDKN2A/B (22%), with 91% concordance rate with their tumor of origin. The mean turnaround-time to chemogram was 6.8 weeks. In 91% of cases, ≥1 hit was identified (gemcitabine (n=20/54), docetaxel (n=18/54) and vinorelbine (n=17/54) with a median of 3 hits/patient [range:0-12]). Our cohort included 34 evaluable patients with full clinical follow-up. We report a chemogram sensitivity of 83.3% and specificity of 92.9%. The overall-response rate and progression-free survival were higher when patients received a "hit" treatment as compared to patients that received a "non-hit" drug (as part of routine management). Finally, we leveraged our PDO collection as a platform for drug validation and combo identification. We tested the anti-KRAS (MRTX1133), alone or combined, and identified a specific synergy with anti-EGFR therapies in KRAS variants.
CONCLUSION
We report the largest prospective study aiming at implementing PDO-based FPM and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround-time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. While this remains to be confirmed in interventional precision oncology trials, PDO collection already provide powerful opportunities for drugs and combinatorial treatment development.
PubMed: 38866343
DOI: 10.1053/j.gastro.2024.05.032 -
Diseases of the Esophagus : Official... Jun 2024The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed...
The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN- status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0-2.9, P = 0.034), ypN+ (HR 1.9, 95% CI 1.1-3.6, P = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0-2.9, P = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required.
PubMed: 38862393
DOI: 10.1093/dote/doae046 -
Aging Jun 2024Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive...
PURPOSE
Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive biomarkers for its early diagnosis and targeted treatment. Disulfidptosis is a newly identified mode of cell death that is characteristic of disulfide stress. Therefore, exploring the correlation between disulfidptosis-related long non-coding RNAs (DRGs-lncRNAs) and patient prognosis can provide new molecular targets for LUAD patients.
METHODS
The study analysed the transcriptome data and clinical data of LUAD patients in The Cancer Genome Atlas (TCGA) database, gene co-expression, and univariate Cox regression methods were used to screen for DRGs-lncRNAs related to prognosis. The risk score model of lncRNA was established by univariate and multivariate Cox regression models. TIMER, CIBERSORT, CIBERSORT-ABS, and other methods were used to analyze immune infiltration and further evaluate immune function analysis, immune checkpoints, and drug sensitivity. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of DRGs-lncRNAs in LUAD cell lines.
RESULTS
A total of 108 lncRNAs significantly associated with disulfidptosis were identified. A prognostic model was constructed by screening 10 lncRNAs with independent prognostic significance through single-factor Cox regression analysis, LASSO regression analysis, and multiple-factor Cox regression analysis. Survival analysis of patients through the prognostic model showed that there were obvious survival differences between the high- and low-risk groups. The risk score of the prognostic model can be used as an independent prognostic factor independent of other clinical traits, and the risk score increases with stage. Further analysis showed that the prognostic model was also different from tumor immune cell infiltration, immune function, and immune checkpoint genes in the high- and low-risk groups. Chemotherapy drug susceptibility analysis showed that high-risk patients were more sensitive to Paclitaxel, 5-Fluorouracil, Gefitinib, Docetaxel, Cytarabine, and Cisplatin. Additionally, RT-PCR analysis demonstrated differential expression of DRGs-lncRNAs between LUAD cell lines and the human bronchial epithelial cell line.
CONCLUSIONS
The prognostic model of DRGs-lncRNAs constructed in this study has certain accuracy and reliability in predicting the survival prognosis of LUAD patients, and provides clues for the interaction between disulfidptosis and LUAD immunotherapy.
Topics: Humans; RNA, Long Noncoding; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Immunotherapy; Male; Female; Cell Line, Tumor; Transcriptome; Middle Aged
PubMed: 38862217
DOI: 10.18632/aging.205911 -
Journal of Biomaterials Science.... Jun 2024Docetaxel is one of the most effective and safe chemotherapy drugs according to the World Health Organization, but its clinical use has been discontinued due to its...
Docetaxel is one of the most effective and safe chemotherapy drugs according to the World Health Organization, but its clinical use has been discontinued due to its various side effects. To reduce these side effects, the amount of docetaxel drug should be kept at the most effective level, it should be monitored in body fluids. Due to the limitations of traditional analytical methods used for this purpose, such as expensive and low sensitivity, labor-intensive and time-consuming complex preliminary preparation, efficient methods are required for the determination of the docetaxel level in the body. The increasing demand for the development of personalized therapy has recently spurred significant research into biosensors for the detection of drugs and other chemical compounds. In this study, an electrochemical-based portable nanobiosensor system was developed for the rapid, low-cost, and sensitive determination of docetaxel. In this context, mg-p(HEMA)-IMEO nanoparticles to be used as nanobiosensor bioactive layer was synthesized, characterized, and docetaxel determination conditions were optimized. According to the results obtained, the developed nanobiosensor system can detect docetaxel with a sensitivity of 2.22 mg/mL in a wide calibration range of 0.25-10 mg/mL, in only 15 min, in mixed media such as commercially available artificial blood serum and urine. determined. We concluded that the developed nanobiosensor system can be successfully used in routine drug monitoring as a low-cost biomedical device capable of direct, rapid, and specific drug determination within the scope of personalized treatment, providing point-of-care testing.
PubMed: 38859628
DOI: 10.1080/09205063.2024.2356965 -
Cell & Bioscience Jun 2024Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated...
BACKGROUND
Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown.
METHODS
Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy.
RESULTS
CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9-Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth.
CONCLUSIONS
We propose a novel regulatory paradigm in which the activation of CDK7/CDK9-Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.
PubMed: 38858714
DOI: 10.1186/s13578-024-01260-2 -
Biomedical Materials (Bristol, England) Jun 2024Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a...
Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a crucial challenge. In this study, we synthesize and construct a glutathione (GSH) and acid dual-responsive bismuth-based nano-delivery platform (BOD), aiming for sonodynamic enhancement of docetaxel (DTX)-mediated tumor therapy. The bismuth nanomaterial can generate multiple reactive oxygen species under ultrasound stimulation. Furthermore, the loading of DTX to form BOD effectively reduces the toxicity of DTX in the bloodstream, ensuring its cytotoxic effect is predominantly exerted at the tumor site. DTX can be well released in high expression of GSH and acidic tumor microenvironment. Meanwhile, ultrasound can also promote the release of DTX. Results from bothandexperiments substantiate that the synergistic therapy involving chemotherapy and sonodynamic therapy significantly inhibits the growth and proliferation of tumor cells. This study provides a favorable paradigm for developing a synergistic tumor treatment platform for tumor microenvironment response and ultrasound-promoted drug release.
Topics: Bismuth; Animals; Glutathione; Docetaxel; Mice; Humans; Antineoplastic Agents; Cell Line, Tumor; Ultrasonic Therapy; Tumor Microenvironment; Reactive Oxygen Species; Neoplasms; Mice, Inbred BALB C; Drug Liberation; Nanoparticles; Female
PubMed: 38857606
DOI: 10.1088/1748-605X/ad565c