AM-18002, a derivative of natural anmindenol A, enhances radiosensitivity in mouse breast cancer cells.

Natural anmindenol A isolated from the marine-derived bacteria Streptomyces sp. caused potent inhibition of inducible nitric oxide synthase without any significant cytotoxicity. This compound consists of a structurally unique 3,10-dialkylbenzofulvene skeleton. We previously synthesized and screened the novel derivatives of anmindenol A and identified AM-18002, an anmindenol A derivative, as a promising anticancer agent. The combination of AM-18002 and ionizing radiation (IR) improved anticancer effects, which were exerted by promoting apoptosis and inhibiting the proliferation of FM3A mouse breast cancer cells. AM-18002 increased the production of reactive oxygen species (ROS) and was more effective in inducing DNA damage. AM-18002 treatment was found to inhibit the expansion of myeloid-derived suppressor cells (MDSC), cancer cell migration and invasion, and STAT3 phosphorylation. The AM-18002 and IR combination synergistically induced cancer cell death, and AM-18002 acted as a potent anticancer agent by increasing ROS generation and blocking MDSC-mediated STAT3 activation in breast cancer cells.

Real-world incidence and risk factors of bortezomib-related cardiovascular adverse events in patients with multiple myeloma.

BACKGROUND: Although most studies on the cardiovascular toxicity of proteasome inhibitors have focused on carfilzomib, the risk of cardiotoxicity associated with bortezomib remains controversial. This study aimed to evaluate the incidence and risk factors of cardiovascular adverse events (CVAEs) associated with bortezomib in patients with multiple myeloma in a real-world setting. METHODS: This cross-sectional study included patients who were treated with bortezomib at a tertiary hospital in South Korea. CVAEs, defined as hypertension, arrhythmia, heart failure, myocardial infarction, pulmonary arterial hypertension, angina, and venous thromboembolism, were detected using cardiac markers, ECG, echocardiography, medications, or documentation by clinicians. The patients were observed for at least 6 months and up to 2 years after starting bortezomib administration. RESULTS: Among the 395 patients, 20.8% experienced CVAEs of any grade, and 14.7% experienced severe adverse events. The median onset time for any CVAE was 101.5 days (IQR, 42-182 days), and new-onset/worsened hypertension was the most prevalent CVAE. The risk of CVAEs increased in patients with a body mass index lower than 18.5 (adjusted HR (aHR) 3.50, 95% confidence interval (CI) 1.05-11.72), light chain (1.80, 1.04-3.13), and IgD (4.63, 1.06-20.20) as the multiple myeloma subtype, baseline stroke (4.52, 1.59-12.80), and hypertension (1.99, 1.23-3.23). However, CVAEs did not significantly affect the 2-year overall survival and progression-free survival. CONCLUSION: Approximately 15% of the Korean patients treated with bortezomib experienced severe CVAEs. Thus, patients, especially those with identified risk factors, should be closely monitored for CVAE symptoms during bortezomib treatment.

Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF-κB pathway, and elevated MMP13 expression.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

Development of a claims-based risk-scoring model to predict emergency department visits in older patients receiving anti-neoplastic therapy.

This study developed and validated a risk-scoring model, with a particular emphasis on medication-related factors, to predict emergency department (ED) visits among older Korean adults (aged 65 and older) undergoing anti-neoplastic therapy. Utilizing national claims data, we constructed two cohorts: the development cohort (2016-2018) with 34,642 patients and validation cohort (2019) with 10,902 patients. The model included a comprehensive set of predictors: demographics, cancer type, comorbid conditions, ED visit history, and medication use variables. We employed the least absolute shrinkage and selection operator (LASSO) regression to refine and select the most relevant predictors. Out of 120 predictor variables, 12 were integral to the final model, including seven related to medication use. The model demonstrated acceptable predictive performance in the validation cohort with a C-statistic of 0.76 (95% CI 0.74-0.77), indicating reasonable calibration. This risk-scoring model, after further clinical validation, has the potential to assist healthcare providers in the effective management and care of older patients receiving anti-neoplastic therapy.

Downregulation of complement factor H attenuates the stemness of MDA­MB­231 breast cancer cells via modulation of the ERK and p38 signaling pathways.

The complement system is a powerful innate immune system deployed in the immediate response to pathogens and cancer cells. Complement factor H (CFH), one of the regulators involved in the complement cascade, can interrupt the death of target cells. Certain types of cancer, such as breast cancer, can adopt an aggressive phenotype, such as breast cancer stem cells (BCSCs), through enhancement of the defense system against complement attack by amplifying various complement regulators. However, little is known about the association between CFH and BCSCs. In the present study, the roles of CFH in the CSC characteristics and radioresistance of MDA-MB-231 human breast cancer cells were investigated. CFH knockdown in MDA-MB-231 cells decreased the viability of the cells upon complement cascade activation. Notably, CFH knockdown also decreased cell survival and suppressed mammosphere formation, cell migration and cell invasion by attenuating radioresistance. Additionally, CFH knockdown further enhanced irradiation-induced apoptosis through G2/M cell cycle arrest. It was also discovered that CFH knockdown attenuated the aggressive phenotypes of cancer cells by regulating CSC-associated gene expression. Finally, by microarray analysis, it was found that the expression of erythrocyte membrane protein band 4.1-like 3 (EPB41L3) was markedly increased following CFH knockdown. EPB41L3 inhibited ERK and activated the p38 MAPK signaling pathway. Taken together, these results indicated that CFH knockdown attenuated CSC properties and radioresistance in human breast cancer cells via controlling MAPK signaling and through upregulation of the tumor suppressor, EPB41L3.

Study Protocol for the Evaluation of Multidisciplinary Medication Reconciliation Service in Adult Patients Undergoing Thoracic and Cardiovascular Surgery (The MERITS Study): A Single-Center Controlled before-and-after Study.

Medication reconciliation (MR), which is widely implemented worldwide, aims to improve patient safety to reduce the medication errors during care transition. Despite its widespread use, MR has not yet been implemented in the Republic of Korea, and its effectiveness has not been studied. We aimed to evaluate the impact of a multidisciplinary MR service in older patients undergoing thoracic and cardiovascular surgery. This is a single-center, prospective, controlled, before-and-after study of adult patients taking at least one chronic oral medication. Depending on the period of each patient's participation, they will be allocated to an intervention group or control group. Patients in the intervention group will receive multidisciplinary MR, and those in the control group will receive usual care. The primary outcome is to assess the impact of the MR service on medication discrepancies between the best possible medication history and medication orders at care transition. Secondary outcomes include the incidence rate of medication discrepancies at each transition, the discrepancy rate between the sources of information, the impact of MR on medication appropriateness index score, drug-related problems, 30-day mortality, the emergency department visit rate, readmission rate after discharge, the rate and acceptability of pharmacists' intervention during hospitalization, and patients' satisfaction.

Risk Factors for Emergency Department Presentations after the Initiation of Opioid Analgesics in Non-Cancer Patients in Korea: A Nationwide Study.

Background and Objectives: Opioid use in Korea is lower than in other developed countries. However, recent studies have reported an increase in opioid prescriptions and the number of chronic opioid users. The current status of adverse events (AEs) associated with opioid analgesics in Korea is unclear. This nested case-control study aimed to evaluate the influence of opioid analgesic use patterns on all emergency department (ED) visits and opioid-related ED visits after opioid analgesic initiation using the national claims database. Materials and Methods: Adult non-cancer patients who initiated non-injectable opioid analgesics (NIOA) between January 2017 and June 2018 were included. We defined the case group as patients who visited the ED within six months of opioid initiation, and the control group was selected in a 1:1 ratio using an exact matching method. Results: A total of 97,735 patients (13.58%) visited the ED within six months of NIOA initiation. Nearly 32% of cases were linked to opioid-related AEs. The most frequent AEs were falls and fractures (61.27%). After adjusting for covariates, opioid initiation at the ED was associated with all-cause or opioid-related ED visits (adjusted odds ratio (aOR) = 3.19, 95% confidence interval (CI) = 3.09-3.29; aOR = 3.82, 95% CI = 3.62-4.04, respectively). Chronic NIOA use was associated with all-cause and opioid-related ED visits (aOR = 1.32, 95% CI = 1.23-1.40; aOR = 1.56, 95% CI = 1.39-1.76, respectively). Conclusion: This study found that 13% of non-cancer patients visited the ED within six months of NIOA initiation. In addition, the NIOA use pattern was significantly associated with all-cause and opioid-related ED visits.

Analysis of Medication Errors Reported by Community Pharmacists in the Republic of Korea: A Cross-Sectional Study.

Background and objectives: We aimed to describe medication-related incidents or medication errors (MEs) reported by community pharmacists and analyze the prevalent medications involved. Materials and Methods: We extracted ME reports from databases comprising patient safety incidents reported to the Korean Pharmaceutical Association between January 2013 and June 2021. Medications were analyzed according to the second (therapeutic subgroup) and fifth (chemical substance) levels of the Anatomical Therapeutic Chemical classification. Results: A total of 9046 MEs were identified, most of which were near miss reports (88.3%). Among the errors that reached the patients (521 cases), harmful incidents accounted for 76.8%. Most MEs occurred during prescription (89.5%), while harmful MEs occurred mainly during dispensing (73.3%). In the prescription step, wrong drugs (44.8%), dosing errors (27.0%), and wrong durations (14.0%) were common. Anti-inflammatory and anti-rheumatic products (M01), drugs for acid-related disorders (A02), and antihistamines for systemic use (R06) were the most frequently reported medication classes involved. Harmful incidents were most common for dosing errors (31.0%) and wrong drugs (26.8%) and were common with warfarin, levothyroxine, and glimepiride. Conclusions: The MEs reported by community pharmacists were mainly prescribing errors, most of which were rectified before reaching patients. The prevalent medications involved in harmful errors include anti-diabetic, anti-thrombotic, and anti-inflammatory agents.

Trends in potentially inappropriate opioid prescribing and associated risk factors among Korean noncancer patients prescribed non-injectable opioid analgesics.

Introduction: The aim of this study was to investigate trends in the prevalence of potentially inappropriate opioid prescribing (PIOP) and identify potential risk factors among Korean noncancer patients. Methods: We conducted a cross-sectional study of annual national patient sample data from the Korean Health Insurance Review and Assessment Service (HIRA-NPS) for the period 2012-2018. Noncancer patients who were prescribed non-injectable opioid analgesics (NIOAs) at least once were included. The proportion of patients with at least one PIOP in terms of concurrent use of benzodiazepines or gabapentinoids, substance use disorder, treatment duration, and dosage was evaluated. Multivariable logistic regression was performed to identify the risk factors associated with PIOP. Results: Of the 9,772,503 noncancer patients, 1,583,444 (16.2%) were prescribed NIOAs at least once. Among them, 15.7% were exposed to PIOP, and the prevalence was much higher (31.6%) in the elderly group (age: ⩾65 years). The prevalence of PIOP increased 1.1-fold over 7 years (14.8-16.8%) among the total NIOA users and was more pronounced in non-tramadol NIOA users (a 1.5-fold increase, from 13.2% to 19.4%). Multivariable logistic regression indicated that older age, beneficiaries of medical aid or national meritorious service, exposure to polypharmacy, psychological disorder, chronic pain indication, and concomitant sedative use were independently associated with higher odds of PIOP. Discussion and Conclusion: We found that the prevalence of PIOP was 15.7% among Korean noncancer patients, and it increased over the 7-year study period. This increasing trend is alarming because it was more drastic with non-tramadol NIOAs compared with that with tramadol. Several patient-level risk factors associated with PIOP would be useful in targeted management strategies for the safe use of opioids. Plain Language Summary: Potentially inappropriate opioid prescribing and related risk factors among noncancer patients prescribed non-injectable opioids in Korea In Korea, the prevalence of non-injectable opioid analgesic (NIOA) use in noncancer patients steadily increased from 15.3% in 2012 to 17.1% in 2018.Also, the prevalence of potentially inappropriate opioid prescribing (PIOP) increased from 14.8% in 2012 to 16.8% in 2018.The following factors were associated with a markedly increased risk of PIOP: age, beneficiaries of medical aid or national meritorious service, polypharmacy, psychological disorder, chronic pain, and concomitant medications.

G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer.

Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-ß superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.

Risk factors of chronic opioid use after surgical procedures in noncancer patients: A nationwide case-control study.

BACKGROUND: Surgery is an indication for opioid prescription in noncancer patients, and chronic use of opioids is associated with overdose and abuse. OBJECTIVES: We aimed to evaluate the prevalence and risk factors associated with chronic opioid use (COU) following surgery among noncancer patients. DESIGN: A nationwide case-control study. SETTING: Retrospective analysis of the annual national patient sample data from 2012 to 2018 in South Korea. PATIENTS: Adults without cancer who had undergone surgery and received noninjectable opioids during hospital stay. MAIN OUTCOME MEASURES: COU during 3 months following surgery. RESULTS: A total of 15 543 participants were included, and the prevalence overall and in opioid-naïve users was 8.1 and 5.7%, respectively. Prior exposure patterns of opioids [intermittent user, adjusted odds ratio (aOR) 2.35; 95% CI, 2.00 to 2.77, and continuous user, aOR 8.58; 95% CI, 6.54 to 11.24] and concomitant use of benzodiazepine (in continuous user, aOR 18.60; 95% CI 11.70 to 29.55) were strongly associated with COU compared with naïve users. Morphine milligram equivalent, type of opioid strength at discharge and prescription of nonopioid analgesics at discharge were also associated with COU. Compared with minor surgery, knee (aOR 1.49; 95% CI 1.17 to 1.89), spine (aOR 1.65; 95% CI 1.33 to 2.06) and shoulder (aOR 2.54; 95% CI 1.97 to 3.27) procedures showed a significantly positive association with COU. Sensitivity analysis in opioid-naïve patients showed similar results. CONCLUSION: About 8.1% of noncancer patients who had undergone surgery and were prescribed noninjectable opioids became chronic opioid users in Korea. Identified risk factors could be used to derive strategies for safe opioid use in noncancer patients in the future.

Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer.

Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the enzyme aromatase, targeting the activity of this enzyme represents a therapeutic option. The pineal hormone melatonin may exert a suppressive role on aromatase activity, leading to reduced estrogen biosynthesis. A melatonin-mediated decrease in the expression of aromatase promoters and associated genes would provide suitable evidence of this molecule's efficacy as an aromatase inhibitor. Furthermore, melatonin intensifies radiation-induced anti-aromatase effects and counteracts the unwanted disadvantages of chemotherapeutic agents. In this manner, this review summarizes the inhibitory role of melatonin in aromatase action, suggesting its role as a possible oncostatic molecule in breast cancer.

Inhibitory effect of ginsenoside Rg3 on cancer stemness and mesenchymal transition in breast cancer via regulation of myeloid-derived suppressor cells.

Ginsenoside Rg3 (Rg3) has been studied in several cancer models and is suggested to act through various pharmacological effects. We investigated the anticancer properties of Rg3 through myeloid-derived suppressor cell (MDSC) modulation in FM3A mouse mammary carcinoma cells. The effects of Rg3 on MDSCs and consequent changes in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) were evaluated by diverse methods. MDSCs promoted cancer by enhancing breast cancer stemness and promoting EMT. Rg3 at a dose without obvious cytotoxicity downregulated MDSCs and repressed MDSC-induced cancer stemness and EMT. Mechanistic investigations suggested that these inhibitory effects of Rg3 on MDSCs and corresponding cancer progression depend upon suppression of the STAT3-dependent pathway, tumor-derived cytokines, and the NOTCH signaling pathway. In a mouse model, MDSCs accelerated tumor progression, and Rg3 delayed tumor growth, which is consistent with the results of in vitro experiments. These results indicated that Rg3 could effectively inhibit the progression of breast cancer. The anticancer effect of Rg3 might be partially due to its downregulation of MDSCs and consequent repression of cancer stemness and EMT in breast cancer. Hence, we suggest the regulation of MDSCs through Rg3 treatment as an effective therapeutic strategy for breast cancer patients.

DBC1 regulates Wnt/ß-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer.

Metastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function of MACC1 in various types of human malignancies, regulatory mechanisms underlying MACC1 expression remain unclear. Here we report that MACC1 is a direct target of Wnt/ß-catenin signaling pathway in colon cancer cells and that DBC1 functions as a coactivator for Wnt-mediated MACC1 expression by promoting the activity of a LEF1/ß-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/ß-catenin complex formation on the MACC1 enhancer and for long-distance enhancer-promoter interaction of the MACC1 locus. MACC1 expression was increased in colonosphere cells compared to adherent colon cancer cells, and DBC1 overexpression further increased MACC1 expression in colonospheres and promoted sphere-forming abilities of colon cancer cells and drug resistance of colonospheres. Importantly, expressions of MACC1 and DBC1 are positively correlated with each other, upregulated in high-risk groups of colorectal cancer patients, and associated with poor survival. Our results establish MACC1 as a transcriptional target of Wnt/ß-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/ß-catenin-MACC1 signaling axis.

EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells.

Cancer stem-like cells (CSCs) may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs) play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC) with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC. We selected CD44 and EpCAM peptides that bind to HLA-A2 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Our data showed that CSCs express high levels of tumor-associated antigens (TAAs) as well as major histocompatibility complex (MHC) molecules. Pulsing DCs with CD44 and EpCAM peptides resulted in the efficient generation of mature DCs (mDCs), thus enhancing T cell stimulation and generating potent cytotoxic T lymphocytes (CTLs). The activation of CSC peptide-specific immune responses by the DC vaccine in combination with standard chemotherapy may provide better clinical outcomes in advanced carcinomas.

Downregulation of UHRF1 increases tumor malignancy by activating the CXCR4/AKT-JNK/IL-6/Snail signaling axis in hepatocellular carcinoma cells.

UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.

Carbon ion irradiation abrogates Lin28B-induced X-ray resistance in melanoma cells.

The Lin28/let-7 axis plays an important role in tumor initiation and developmental processes. Lin28B is upregulated in a variety of cancers, and its overexpression enhances cancer cell proliferation and radioresistance through the suppression of let-7 micro RNA expression. In this study, we investigated the role of the Lin28/let7 axis as a target for radiosensitization of melanoma cancer cells. The overexpression of Lin28B reduced mature let-7 microRNA expression in melanoma cell lines, and enhanced the sphere-forming ability of melanoma cell lines, which is a characteristic of cancer stem cell (CSC) populations. Interestingly, Lin28B-overexpressed melanoma cells were more resistant to X-ray irradiation than control cells, and Lin28B-induced radioresistance was abolished after carbon ion irradiation. Consistent with these results, Lin28B overexpression reduced the numbers of γH2A.X foci after X-ray irradiation, whereas carbon ion irradiation had no such effect. Our results suggest that a carbon ion beam is more effective than an X-ray beam in terms of killing cancer cells, possibly due to elimination of CSC populations.

Accumulation of low-dose BIX01294 promotes metastatic potential of U251 glioblastoma cells.

BIX01294 (Bix) is known to be a euchromatic histone-lysine N-methyltransferase 2 inhibitor and treatment with Bix suppresses cancer cell survival and proliferation. In the present study, it was observed that sequential treatment with low-dose Bix notably increases glioblastoma cell migration and metastasis. It was demonstrated that U251 cells sequentially treated with low-dose Bix exhibited induced characteristic changes in critical epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, ß-catenin and zinc finger protein SNAI2. Notably, sequential treatment with Bix also increased the expression of cancer stem cell-associated markers, including sex determining region Y-box 2, octamer-binding transcription factor 4 and cluster of differentiation 133. Neurosphere formation was significantly enhanced in cells sequentially treated with Bix, compared with control cells (control: P=0.011; single treatment of Bix, P=0.045). The results of the present study suggest that accumulation of low-dose Bix enhanced the migration and metastatic potential of glioblastoma cells by regulating EMT-associated gene expression, which may be the cause of the altered properties of glioblastoma stem cells.

The resveratrol analog HS-1793 enhances radiosensitivity of mouse-derived breast cancer cells under hypoxic conditions.

Tumor hypoxia is associated with treatment resistance, cell proliferation, and metastatic potential, all of which contribute to a poor prognosis. Resveratrol [RES (trans-3,4',5-trihydroxystilbene)], a naturally occurring polyphenol, is enriched in grapes and red wine. This study investigated whether the resveratrol analog HS-1793 modulates the hypoxic status and the level of perfusion in mouse breast cancer FM3A cells. Our data show that HS-1793 decreased the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor protein under hypoxic conditions in FM3A cells. HS-1793 improved perfusion and hypoxic status in tumor tissues and inhibited angiogenesis through HIF-1α suppression in mice. Moreover, HS-1793 inhibited hypoxia-induced cancer stem cell properties and enhanced ionizing radiation-induced apoptosis in hypoxic FM3A cells. Collectively, the resveratrol analog HS-1793 might act as a potent radiosensitizer and be a useful adjuvant agent against radiotherapy-resistant hypoxic cells in solid tumors.

Low-dose irradiation promotes Rad51 expression by down-regulating miR-193b-3p in hepatocytes.

Current evidence indicates that there is a relationship between microRNA (miRNA)-mediated gene silencing and low-dose irradiation (LDIR) responses. Here, alterations of miRNA expression in response to LDIR exposure in male BALB/c mice and three different types of hepatocytes were investigated. The miRNome of the LDIR-exposed mouse spleens (0.01 Gy, 6.5 mGy/h) was analyzed, and the expression of miRNA and mRNA was validated by qRT-PCR. Western blotting, chromatin immunoprecipitation (ChIP), and luciferase assays were also performed to evaluate the interaction between miRNAs and their target genes and to gain insight into the regulation of miRNA expression. The expression of miRNA-193b-3p was down-regulated in the mouse spleen and liver and in various hepatocytes (NCTC, Hepa, and HepG2 cell lines) in response to LDIR. The down-regulation of miR-193b-3p expression was caused by histone deacetylation on the miR-193b-3p promoter in the HepG2 cells irradiated with 0.01 Gy. However, the alteration of histone deacetylation and miR-193b-3p and Rad51 expression in response to LDIR was restored by pretreatment with N-acetyl-cyctein. In conclusion, we provide evidence that miRNA responses to LDIR include the modulation of cellular stress responses and repair mechanisms.