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Yakugaku Zasshi : Journal of the... 2023Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University,...
[Modulation of Expression of Drug Metabolizing Enzymes and Augmentation of Anti-cancer Drug Effects: Through Epigenetics and Three-dimensional Cancer Cell Culture Systems].
Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.
Topics: Humans; Cytochrome P-450 CYP1A2; Irinotecan; Pharmaceutical Preparations; Antineoplastic Agents; Colonic Neoplasms; Decitabine; Fluorouracil; Epigenesis, Genetic; DNA; Cell Culture Techniques; Methyltransferases
PubMed: 38044107
DOI: 10.1248/yakushi.23-00158 -
Therapeutic Advances in Hematology 2023The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate...
Low-dose decitabine for previously untreated acute myeloid leukemia ineligible for intensive chemotherapy aged 65 years or older: a prospective study based on comprehensive geriatric assessment.
BACKGROUND
The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy.
OBJECTIVES
We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment.
DESIGN
We performed a prospective, multicenter, open-label, and non-randomized study.
METHODS
Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity.
RESULTS
Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65-90) years. The median follow-up time was 22.2 (range, 4.6-38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment.
CONCLUSION
In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.
PubMed: 38033755
DOI: 10.1177/20406207231208979 -
Haematologica Apr 2024
Topics: Humans; Chromosome Deletion; Chromosomes, Human, Pair 5; Decitabine; Lenalidomide; Mutation; Myelodysplastic Syndromes; Salvage Therapy; Tumor Suppressor Protein p53
PubMed: 38031760
DOI: 10.3324/haematol.2023.284547 -
International Journal of Ophthalmology 2023To evaluate the therapeutic effect of folic acid combined with decitabine on diabetic mice.
AIM
To evaluate the therapeutic effect of folic acid combined with decitabine on diabetic mice.
METHODS
The diabetic model of mice were randomly divided into model group, folic acid group, decitabine group, folic acid combined with decitabine group, and C57 mice as normal control group. The density of retinal blood vessels and retinal thickness were detected by fundus photography and optical coherence tomography, respectively. Pathological changes of retina were observed by hematoxylin-eosin (HE) staining. The homocysteine (Hcy) in serum was detected by enzyme linked immunosorbent assay (ELISA). TdT-mediated dUTP nick-end labeling (TUNEL) was used to detect apoptosis in retinal tissue. Evans blue dye was used to detect the permeability of retinal blood vessels. The platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor receptor (VEGFR) protein were detected by Western blot. The 3-nitrotyrosine (3-NT) and 4-hydroxynonanine (4-HNE) were detected by immunohistochemistry.
RESULTS
The density of retinal blood vessels, retinal thickness, retinal vascular permeability and the proportion of apoptotic cells of retinal tissue in the model group increased significantly than control group (<0.05). The Hcy in serum and the levels of CD31, VEGFR, 3-NT, and 4-HNE in retinal tissue increased significantly in the model group (<0.01). Folic acid and decitabine both reversed these changes significantly, and the combination of the folic acid and decitabine worked best.
CONCLUSION
The combination of folic acid and decitabine has a more significant protective effect on the retina in diabetic mice.
PubMed: 38028519
DOI: 10.18240/ijo.2023.11.05 -
Frontiers in Immunology 2023Triple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy...
INTRODUCTION
Triple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy (PDT) is a focal therapy that uses light to activate a photosensitizing agent and induce a cytotoxic effect. 5-aza-2'-deoxycytidine (5-ADC) is a clinically approved immunomodulatory chemotherapy agent. The mechanism of the combination therapy using PDT and 5-ADC in evoking an anti-tumour response is not fully understood.
METHODS
The present study examined whether a single dose of 5-ADC enhances the cytotoxic and anti-tumour immune effect of low dose PDT with verteporfin as the photosensitiser in a TNBC orthotopic syngeneic murine model, using the triple negative murine mammary tumour cell line 4T1. Histopathology analysis, digital pathology and immunohistochemistry of treated tumours and distant sites were assessed. Flow cytometry of splenic and breast tissue was used to identify T cell populations. Bioinformatics were used to identify tumour immune microenvironments related to TNBC patients.
RESULTS
Functional experiments showed that PDT was most effective when used in combination with 5-ADC to optimize its efficacy. 5-ADC/PDT combination therapy elicited a synergistic effect and was significantly more cytotoxic than monotherapies on 4T1 tumour cells. For tumour therapy, all types of treatments demonstrated histopathologically defined margins of necrosis, increased T cell expression in the spleen with absence of metastases or distant tissue destruction. Flow cytometry and digital pathology results showed significant increases in CD8 expressing cells with all treatments, whereas only the 5-ADC/PDT combination therapy showed increase in CD4 expression. Bioinformatics analysis of in silico publicly available TNBC data identified BCL3 and BCL2 as well as the following anti-tumour immune response biomarkers as significantly altered in TNBC compared to other breast cancer subtypes: GZMA, PRF1, CXCL1, CCL2, CCL4, and CCL5. Interestingly, molecular biomarker assays showed increase in anti-tumour response genes after treatment. The results showed concomitant increase in BCL3, with decrease in BCL2 expression in TNBC treatment. In addition, the treatments showed decrease in PRF1, CCL2, CCL4, and CCL5 genes with 5-ADC and 5-ADC/PDT treatment in both spleen and breast tissue, with the latter showing the most decrease.
DISCUSSION
To our knowledge, this is the first study that shows which of the innate and adaptive immune biomarkers are activated during PDT related treatment of the TNBC 4T1 mouse models. The results also indicate that some of the immune response biomarkers can be used to monitor the effectiveness of PDT treatment in TNBC murine model warranting further investigation in human subjects.
Topics: Humans; Animals; Mice; Verteporfin; Triple Negative Breast Neoplasms; Decitabine; Disease Models, Animal; Photosensitizing Agents; Antineoplastic Agents; Photochemotherapy; Biomarkers; Proto-Oncogene Proteins c-bcl-2; Tumor Microenvironment
PubMed: 38022682
DOI: 10.3389/fimmu.2023.1188087 -
MedComm Dec 2023Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome...
Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.
PubMed: 38020717
DOI: 10.1002/mco2.428 -
Clinical Epigenetics Nov 2023Elderly patients with AML ineligible for induction have a dismal prognosis; hence disease stabilization is a primary treatment goal. This case of a 75-year-old patient...
Elderly patients with AML ineligible for induction have a dismal prognosis; hence disease stabilization is a primary treatment goal. This case of a 75-year-old patient with secondary AML receiving the combination of decitabine and ATRA (within the DECIDER trial, NCT00867672) demonstrates an above-average survival. The therapy administered over 52 cycles led to complete molecular and hematological remission and resulted in 5.3 years overall survival. Clonal evolution of the leukemic clone could be demonstrated using DNA sequencing methods. According to the literature, this case constitutes the longest continued HMA exposure in an elderly AML patient ineligible for standard chemotherapy.
Topics: Humans; Aged; Decitabine; Tretinoin; DNA Methylation; Prognosis; Leukemia, Myeloid, Acute; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38012682
DOI: 10.1186/s13148-023-01596-5 -
Cancer Cell International Nov 2023Lack of Schlafen family member 11 (SLFN11) expression has been recently identified as a dominant genomic determinant of response to DNA damaging agents in numerous...
BACKGROUND
Lack of Schlafen family member 11 (SLFN11) expression has been recently identified as a dominant genomic determinant of response to DNA damaging agents in numerous cancer types. Thus, several strategies aimed at increasing SLFN11 are explored to restore chemosensitivity of refractory cancers. In this study, we examined various approaches to elevate SLFN11 expression in breast cancer cellular models and confirmed a corresponding increase in chemosensitivity with using the most successful efficient one. As oncogenic transcriptomic downregulation is often driven by methylation of the promotor region, we explore the demethylation effect of 5-aza-2'-deoxycytidine (decitabine), on the SLFN11 gene. Since SLFN11 has been reported as an interferon inducible gene, and interferon is secreted during an active anti-tumor immune response, we investigated the in vitro effect of IFN-γ on SLFN11 expression in breast cancer cell lines. As a secondary approach to pick up cross talk between immune cells and SLFN11 expression we used indirect co-culture of breast cancer cells with activated PBMCs and evaluated if this can drive SLFN11 upregulation. Finally, as a definitive and specific way to modulate SLFN11 expression we implemented SLFN11 dCas9 (dead CRISPR associated protein 9) systems to specifically increase or decrease SLFN11 expression.
RESULTS
After confirming the previously reported correlation between methylation of SLFN11 promoter and its expression across multiple cell lines, we showed in-vitro that decitabine and IFN-γ could increase moderately the expression of SLFN11 in both BT-549 and T47D cell lines. The use of a CRISPR-dCas9 UNISAM and KRAB system could increase or decrease SLFN11 expression significantly (up to fivefold), stably and specifically in BT-549 and T47D cancer cell lines. We then used the modified cell lines to quantify the alteration in chemo sensitivity of those cells to treatment with DNA Damaging Agents (DDAs) such as Cisplatin and Epirubicin or DNA Damage Response (DDRs) drugs like Olaparib. RNAseq was used to elucidate the mechanisms of action affected by the alteration in SLFN11 expression. In cell lines with robust SLFN11 promoter methylation such as MDA-MB-231, no SLFN11 expression could be induced by any approach.
CONCLUSION
To our knowledge this is the first report of the stable non-lethal increase of SLFN11 expression in a cancer cell line. Our results show that induction of SLFN11 expression can enhance DDA and DDR sensitivity in breast cancer cells and dCas9 systems may represent a novel approach to increase SLFN11 and achieve higher sensitivity to chemotherapeutic agents, improving outcome or decreasing required drug concentrations. SLFN11-targeting therapies might be explored pre-clinically to develop personalized approaches.
PubMed: 38001424
DOI: 10.1186/s12935-023-03144-w -
Clinical Lymphoma, Myeloma & Leukemia Mar 2024We sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with...
BACKGROUND
We sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with refractory anemia with excess blasts (RAEB; an established proxy for higher-risk myelodysplastic syndromes/neoplasms) in contemporary and representative real-world settings.
PATIENTS AND METHODS
We used the Surveillance, Epidemiology and End Results (SEER)-Medicare database, a linkage of cancer registry and Medicare claims data, to identify patients aged ≥ 66 years diagnosed with RAEB, between 2009 and 2017 in the United States, and who received AZA or DEC as first-line therapy. Outcomes measured were overall survival (OS), event-free survival (EFS), and incidence of progression-related acute myeloid leukemia (AML).
RESULTS
Of 973 eligible patients, 738 (75.8%) received AZA and 235 (24.2%) received DEC; 6.4% received hematopoietic cell transplantation during follow-up. In the overall population, median OS was 13.9 months (95% confidence interval [CI]: 12.9-15.0), median EFS was 5.2 months (95% CI: 4.9-5.7), and 38.0% of patients progressed to AML. Incidences of AML progression and death were 25.6% and 29.9%, respectively, at Year 1, and 34.3% and 44.8%, respectively, at Year 2. There were no significant differences in clinical benefits between AZA and DEC.
CONCLUSION
Median OS with both HMAs remained significantly shorter than in the AZA-001 clinical trial, highlighting how patient outcomes vary between clinical and real-world settings. Further research is required to understand why these disparities exist.
Topics: Humans; Aged; United States; Anemia, Refractory, with Excess of Blasts; Decitabine; Antimetabolites, Antineoplastic; Medicare; Azacitidine; Leukemia, Myeloid, Acute
PubMed: 37996264
DOI: 10.1016/j.clml.2023.10.010 -
American Journal of Translational... 2023In this comprehensive breast cancer (BC) study, we aimed to identify, validate, and characterize key biomarkers with significant implications in BC diagnosis, prognosis,...
OBJECTIVES
In this comprehensive breast cancer (BC) study, we aimed to identify, validate, and characterize key biomarkers with significant implications in BC diagnosis, prognosis, and as therapeutic targets.
METHODS
Our research strategy involved a multi-level methodology, combining bioinformatic analysis with experimental validation.
RESULTS
Initially, we conducted an extensive literature search to identify BC biomarkers, selecting those with reported accuracies exceeding 20% in specificity and sensitivity. This yielded nine candidate biomarkers, which we subsequently analyzed using Cytoscape to identify a few key biomarkers. Based on the degree method, we denoted four key biomarkers, including progesterone receptor (PGR), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2). Expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that PGR and EGFR exhibited significant (-value < 0.05) down-regulation in BC samples when compared to controls, while ESR1 and ERBB2 showed up-regulation. To strengthen our findings, we collected clinical BC tissue samples from Pakistani patients and performed expression verification using real-time quantitative polymerase chain reaction (RT-qPCR). The results aligned with our initial TCGA dataset analysis, further validating the differential expression of these key biomarkers in BC. Furthermore, we utilized receiver operating characteristic (ROC) curves to demonstrate the diagnostic use of these biomarkers. Our analysis underscored their accuracy and sensitivity as diagnostic markers for BC. Survival analysis using the Kaplan-Meier Plotter tool revealed a prognostic significance of PGR, ESR1, EGFR, and ERBB2. Their expression levels were associated with poor overall survival (OS) of BC patients, shedding light on their roles as prognostic indicators in BC. Lastly, we explored DrugBank to identify drugs that may reverse the expression patterns , and estradiol, decitabine, and carbamazepine were singled out.
CONCLUSION
Our study gives valuable insight into BC biomarkers, for diagnosis and prognosis. These findings have implications for BC management using personalized and targeted therapeutic approaches for BC patients.
PubMed: 37969199
DOI: No ID Found