Chlorpyrifos-induced suppression of the antioxidative defense system leads to cytotoxicity and genotoxicity in macrophages.

Chlorpyrifos, widely used for pest control, is known to have various harmful effects, although its toxic effects in macrophages and the mechanisms underlying its toxicity remain unclear. The present study investigated the toxic effects of chlorypyrifos in a macrophage cell line. Here, we found that chlorpyrifos induced cytotoxicity and genotoxicity in RAW264.7 macrophages. Moreover, chlorpyrifos induced intracellular ROS production, subsequently leading to lipid peroxidation. Chlorpyrifos reduced the activation of antioxidative enzymes including superoxide dismutase, catalase, and glutathione peroxidase. Chlorpyrifos upregulated HO-1 expression and activated the Keap1-Nrf2 pathway, as indicated by enhanced Nrf2 phosphorylation and Keap1 degradation. Chlorpyrifos exerted effects on the following in a dose-dependent manner: cytotoxicity, genotoxicity, lipid peroxidation, intracellular ROS production, antioxidative enzyme activity reduction, HO-1 expression, Nrf2 phosphorylation, and Keap1 degradation. Notably, N-acetyl-L-cysteine successfully inhibited chlorpyrifos-induced intracellular ROS generation, cytotoxicity, and genotoxicity. Thus, chlorpyrifos may induce cytotoxicity and genotoxicity by promoting intracellular ROS production and suppressing the antioxidative defense system activation in macrophages.

Wogonin induces apoptosis in macrophages by exhibiting cytotoxic and genotoxic effects.

Macrophages play an important role in defending the body against invading pathogens. In the face of pathogens, macrophages become activated and release toxic materials that disrupt the pathogens. Macrophage overactivation can lead to severe illness and inflammation. Wogonin has several therapeutic effects, including anti-inflammatory, anticancer, antioxidant, and neuroprotective effects. No studies have investigated the cytotoxic effects of wogonin at concentrations of more than 0.1 mM in RAW264.7 cells. In this study, RAW 264.7 cells were treated with wogonin, which, at concentrations of more than 0.1 mM, had cytotoxic and genotoxic effects in the RAW264.7 cells, leading to apoptosis and necrosis. Further, wogonin at concentrations of more than 0.1 mM induced caspase-3, caspase-8, and caspase-9 activation and mitochondrial dysfunction and death receptor expression. These results suggest that wogonin induces apoptosis through upstream intrinsic and extrinsic pathways by exhibiting cytotoxic and genotoxic effects.

Cyclizine induces cytotoxicity and apoptosis in macrophages through the extrinsic and intrinsic apoptotic pathways.

Cyclizine, an over-the-counter and prescription antihistamine, finds widespread application in the prevention and treatment of motion sickness, encompassing symptoms such as nausea, vomiting, dizziness, along with its effectiveness in managing vertigo. However, the overuse or misuse of cyclizine may lead to hallucinations, confusion, tachycardia, and hypertension. The molecular mechanisms underlying cyclizine-induced cytotoxicity and apoptosis remain unclear. During the 24 h incubation duration, RAW264.7 macrophages were exposed to different concentrations of cyclizine. Cytotoxicity was assessed through the lactate dehydrogenase assay. Flow cytometry employing annexin V-fluorescein isothiocyanate and propidium iodide was utilized to evaluate apoptosis and necrosis. Caspase activity and mitochondrial dysfunction were evaluated through a fluorogenic substrate assay and JC-1 dye, respectively. Flow cytometry employing fluorogenic antibodies was utilized to evaluate the release of cytochrome c and expression of death receptor, including tumor necrosis factor-α receptor and Fas receptor. Western blotting was utilized to evaluate the expression of the Bcl2 and Bad apoptotic regulatory proteins. The findings unveiled from the present study demonstrated that cyclizine exerted a concentration-dependent effect on RAW264.7 macrophages, leading to the induction of cytotoxicity, apoptosis, and necrosis. This compound further activated the intrinsic apoptotic pathway by inducing mitochondrial dysfunction, Bcl2/Bad exchange expression, cytochrome c liberation, and activation of caspases contained caspase 3, 8, and 9. Moreover, the activation of the extrinsic apoptotic pathway was observed as cyclizine induced the upregulation of death receptors and increased caspase activities. Based on our investigations, it can be inferred that cyclizine prompts cytotoxicity and apoptosis in RAW264.7 macrophages in a concentration-dependent manner by triggering both the intrinsic and extrinsic apoptotic pathways.

Cedrol restricts the growth of colorectal cancer in vitro and in vivo by inducing cell cycle arrest and caspase-dependent apoptotic cell death.

Background: Cedrol is a natural sesquiterpene alcohol found in Cedrus atlantica, which has been proven to have a broad spectrum of biological activities, such as antimicrobial, anti-inflammatory, analgesic, anxiolytic, and anti-cancer effects. However, the underlying anticancer mechanisms and in vivo inhibitory effects of cedrol on colorectal cancer (CRC) have not been elucidated. In the present study, we investigated the anti-CRC potential of cedrol using in vitro and in vivo models. Methods: The effects of cedrol on cell viability, cell cycle progression, and apoptosis of HT-29 and CT-26 cells were detected by MTT, flow cytometry, and TUNEL assays. Western blotting was used to measure protein expression for molecular signaling analyses. Results: Cedrol inhibited HT-29 and CT-26 cell proliferation in a time- and dose-dependent manner, with IC50 values of 138.91 and 92.46 µM, respectively. Furthermore, cedrol induced cell cycle arrest at the G0/G1 phase by regulating the expression of cell cycle regulators, such as CDK4 and cyclin D1, and triggered apoptosis through extrinsic (FasL/caspase-8) and intrinsic (Bax/caspase-9) pathways. In addition, cedrol in combination with the clinical drug 5-fluorouracil exhibited synergistic inhibitory effects on CRC cell growth. Importantly, cedrol treatment suppressed the progression of CRC and improved the survival rate of animals at a well-tolerated dose. Conclusion: These results suggest that cedrol has an anti-cancer potential via induction of cell cycle arrest and apoptosis, and it could be considered as an effective agent for CRC therapy.

Rapid Administration of Antibiotics for Reducing Fever Days in Patients Receiving Hematopoietic Stem Cell Transplantation.

Background and Objectives: Neutropenic fever (NF) is a major cause of mortality and morbidity in patients undergoing hematopoietic stem cell transplantation (HSCT). To date, no study has discussed the relationship of fever days in HSCT with the time between recording the fever and administering antibiotics. This study aimed to examine the association between fever days in HSCT and the time interval between recording the fever and intravenous (IV) antibiotics to the febrile neutropenia patient. Materials and Methods: A total of 22 patients who developed NF after HSCT in one hospital were analyzed. Patients who received IV antibiotics injection within 30 min were categorized in group A and those who received the injection after 30 min were categorized in group B. Fever was defined by an attack with an oral temperature of 38.3 °C. Patients' characteristics and possible risk factors were recorded and analyzed. Results: Groups A and B had 14 and 8 patients, respectively. Patient characteristics, including age, diagnosis, sex, and antibiotics level, were similar between the two groups. The median duration of fever days was 1.5 (range, 1−5) in group A and 6.5 (range, 1−14) in group B (p = 0.003). Multivariant analysis of possible independent impact factors of "fever days in HSCT" was performed. The odds ratio of "antibiotics given time" was 4.00 (95% confidence interval [CI] = 2.26 to 7.22, p = 0.001). The "antibiotics level" did not affect the NF period (odds ratio = −0.80, 95% CI = −2.40 to 1.07, p = 0.453). Conclusions: Rapid IV administration of antibiotics (<30 min after fever attack) can reduce the fever days in patients undergoing HSCT.

Nonsteroidal Anti-Inflammatory Drugs Reduce Second Cancer Risk in Patients With Breast Cancer: A Nationwide Population-Based Propensity Score-Matched Cohort Study in Taiwan.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality in patients with cancer, especially breast cancer, but their influence on second cancer risk is uncertain. This study aimed to examine whether NSAID use is associated with second cancer risk in patients with breast cancer. This population-based propensity score-matched cohort study using Taiwan's National Health Insurance Research Database enrolled patients with newly diagnosed breast cancer (n = 7356) with and without (n = 1839) NSAID therapy from 2000 to 2009. They were followed up until the diagnosis of second cancer, death, or end of 2011. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). The NSAID cohort had a lower incidence rate of second cancer than the non-NSAID cohort (5.57 vs. 9.19 per 1,000 person-years), with an aHR of 0.63 (95% confidence interval (CI) 0.46-0.87). When compared with the non-NSAID cohort, the second cancer incidence was lower in patients taking non-cyclooxygenase 2 inhibitors (aHR 0.67, 95% CI 0.47-0.94) and in those receiving multiple NSAIDs during follow-up (aHR 0.55, 95% CI 0.37-0.84). A dose-response relationship existed in NSAID cumulative days. The findings demonstrate that NSAID use reduces second cancer risk in a dose-dependent manner in patients with primary breast cancer.

Rutin-protected BisGMA-induced cytotoxicity, genotoxicity, and apoptosis in macrophages through the reduction of the mitochondrial apoptotic pathway and induction of antioxidant enzymes.

Bisphenol-A-glycidyldimethacrylate (BisGMA) is a resin monomer frequently used in dentin restorative treatments. The leakage of BisGMA monomer from BisGMA-based polymeric resins can lead to cytotoxicity in macrophages. Rutin has various beneficial bioeffects, including antioxidation and antiinflammation. In this study, we found that pretreatment of RAW264.7 macrophages with rutin-inhibited cytotoxicity induced by BisGMA in a concentration-dependent manner. BisGMA-induced apoptosis, which was detected by levels of phosphatidylserine from the internal to the external membrane and formation of sub-G1, and genotoxicity, which was detected by cytokinesis-blocked micronucleus and single-cell gel electrophoresis assays, were inhibited by rutin in a concentration-dependent manner. Rutin suppressed the BisGMA-induced activation of caspase-3 and -9 rather than caspase-8. Rutin inhibited the activation of the mitochondrial apoptotic pathway, including cytochrome C release and mitochondria disruption, after macrophages were treated with BisGMA. Finally, BisGMA-induced reactive oxygen species (ROS) generation and antioxidant enzyme (AOE) deactivation could be reversed by rutin. Parallel trends were observed in the elevation of AOE activation and inhibition of ROS generation, caspase-3 activity, mitochondrial apoptotic pathway activation, and genotoxicity. These results suggested that rutin suppressed BisGMA-induced cytotoxicity through genotoxicity, the mitochondrial apoptotic pathway, and relatively upstream factors, including reduction of ROS generation and induction of AOE.

Association between statin use and second cancer risk in breast cancer patients: a nationwide population-based cohort study.

PURPOSE: Many studies have revealed that statin therapy reduced mortality in cancer patients, especially in breast cancer, but the effect for second cancer was unclear. We, therefore, performed a comparable cohort study to determine the risk of second cancer in breast cancer patients with statin therapy. METHODS: Using claims data from Taiwan's National Health Insurance Program, this study enrolled newly diagnosed breast cancer patients from 2000 to 2007 with and without statin therapy as the statin (n = 1222) and nonstatin (n = 4888) cohorts, respectively. The nonstatin cohort was propensity score matched by cohort entry year, age, and randomly selected comorbidities. These two cohorts were followed up until the diagnosis of second cancer, death, or the end of 2011. Cox proportional hazard models were used to estimate the hazard ratios. RESULTS: The statin cohort had a lower incidence rate than the nonstatin cohort for second cancer (7.37 vs. 8.36 per 1000 person-years), although the difference was not significant (adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI] 0.65-1.26). Compared with the nonstatin cohort, the second cancer risk was significantly higher for patients taking pravastatin (aHR 2.71, 95% CI 1.19-6.19) but lower for those receiving multiple statin treatment (aHR 0.45, 95% CI 0.25-0.81) and combined lipophilic and hydrophilic type of statin (aHR 0.42, 95% CI 0.20-0.89). The risk was lower for patients receiving a cumulative defined daily dose (cDDD) of > 430 (aHR 0.41, 95% CI 0.19-0.86). CONCLUSION: This study showed that there is little association between statin use and second cancer risk in breast cancer patients.

Older Age and High Serum Ferritin Levels Associated With the Risk of Chronic Cytopenia in Hemodialysis Patients.

Leukopenia or thrombocytopenia is sometimes observed in end-stage renal disease (ESRD) patients, but the association between chronic leukopenia or thrombocytopenia and hemodialysis (HD) is still unclear. We aimed to investigate the incidence of chronic leukopenia or thrombocytopenia in patients with ESRD who received HD and to determine the risk factors of this complication. We retrospectively analyzed ESRD patients treated with HD at Ditmanson Medical Foundation Chia-Yi Christian Hospital in 2018. The risk factors for the occurrence of chronic leukopenia and thrombocytopenia were analyzed by Cox regression models. Of the 473 patients in our study cohort, 46 (9.7%) patients had a hematologic abnormality, including 18 patients with chronic leukopenia, 18 with chronic thrombocytopenia, and 10 with pancytopenia. Multivariate analysis revealed that patient age ≥60 years at the initiation of dialysis was a significant predictor for both chronic leukopenia [adjusted hazard ratio (aHR), 2.71; 95% confidence interval (CI), 1.06-6.89] and chronic thrombocytopenia (aHR, 2.83; 95% CI, 1.08-7.35). Chronic liver disease (aHR, 3.31; 95% CI, 1.27-8.61) and serum ferritin levels >800 mg/dl (aHR, 3.29; 95% CI, 1.29-8.39) were risk factors for chronic thrombocytopenia. A trend showed that vitamin D from intravenous supplementation (aHR, 0.13; 95% CI, 0.01-1.16, P = 0.066) and serum phosphorous level (aHR, 0.73; 95% CI, 0.53-1.02, P = 0.068) may be associated with chronic thrombocytopenia. Our study demonstrated that hematological abnormality was a long-term complication of HD. These results reveal that older patients with HD and high serum ferritin levels are at an elevated risk for chronic cytopenia. Healthcare professionals should be aware of this risk when treating HD patients in order to improve their prognosis.

Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

Long-term safety and efficacy of deferasirox in patients with myelodysplastic syndrome, aplastic anemia and other rare anemia in Taiwan.

OBJECTIVE: Patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemia require chronic blood transfusions which can lead to iron overload and subsequent excess iron-mediated complications. Intensive iron chelation with deferasirox could remove excess iron and can alleviate these events; however, the long-term safety and efficacy in Chinese population are not clearly characterized. This study examined the long-term efficacy and safety of deferasirox in a real-world setting in Taiwan. METHODS: This observational, non-interventional, single-arm, multi-center, phase IV study was designed to collect the safety and clinical information about patients who were treated with deferasirox according to investigator's judgment and in accordance with the general clinical practice. RESULTS: From 2009 to 2011, patients with MDS (N = 38), AA (N = 23), and other rare anemias (N = 18) were enrolled. The mean deferasirox exposure was 17.7 ± 4.02 mg/kg/day. The most common drug-related AEs were skin disorders (32.9%) and gastrointestinal disorders (30.4%), while grade 3-4 AEs were rare (5.1%). In the overall patient population, deferasirox effectively decreased serum ferritin levels at 1 year (P = 0.0154) and 3 years (P = 0.0424) from the baseline. Upon the use of deferasirox, 32.9% patients showed erythroid response and 16.7% patients had platelet response. CONCLUSIONS: For patients with MDS, AA, and other rare anemias, the AEs observed in this 3-year surveillance study with deferasirox were mostly mild or moderate. In addition, the hematological response rate was higher than that in the EPIC study, which primarily enrolled Caucasian patients.

Effect of eribulin on patients with metastatic breast cancer: multicenter retrospective observational study in Taiwan.

PURPOSE: The aim of this study was to confirm the therapeutic role of eribulin on Taiwanese women with metastatic breast cancer. METHODS: This retrospective study examined 449 females who received eribulin between March 2014 and June 2017 at 14 hospitals in Taiwan for treatment of locally advanced or metastatic breast cancer. RESULTS: The survival rate at 24 months was 57.2% (95% CI 51.0-62.9%) and the median time to treatment failure (TTF) was 3.91 months (95% CI 3.45-3.94). A total of 175 patients (40.1%) received eribulin for fewer than 90 days and the others received it for 90 days or more. Eight patients (1.83%) had complete remission, 82 (18.8%) had partial remission, 202 (46.3%) had stable disease, and 144 (33.0%) had progressive disease (PD). Patients' tumors with the luminal A subtype had a significantly better objective response rate. Kaplan-Meier analysis indicated that hormone receptor positivity, luminal A subtype, receipt of eribulin as the 1st to 3rd line therapy, and metastasis to fewer than 4 organs were significantly associated with longer TTF. Stepwise multivariate analysis showed that only receipt of eribulin as the 1st to 3rd line therapy was significantly associated with TTF (HR 1.49, p < 0.001). All toxicities were manageable and only 18 patients (4.1%) discontinued treatment due to adverse events. CONCLUSIONS: Eribulin appears to have better efficacy and cause fewer adverse events, especially neutropenia, in Taiwanese women than Western women.

Efficacy and toxicity of pegylated liposomal doxorubicin-based chemotherapy in early-stage breast cancer: a multicenter retrospective case-control study.

AIM: PEGylated liposomal doxorubicin (PLD) has comparable efficacy and differing toxicity from conventional anthracyclines used to treat advanced breast cancer. This study compared disease-free survival and toxicity between PLD-based and conventional anthracycline-based regimens as adjuvant treatments for early-stage breast cancer. METHODS: We analyzed disease-free survival (DFS) rates, and adverse events in 102 women with early-stage (I-IIIa) breast cancer who received adjuvant PLD-based chemotherapy from 2002 to 2008. Each patient was matched for age, stage at diagnosis, HER-2 expression and hormone therapy use to a patient treated with an epirubicin-based regimen. Fisher's exact and Pearson's chi-square tests were used for categorical data analysis. Kaplan-Meier analysis and Cox regression models were used to analyze DFS. RESULTS: DFS at 5 years was 81.3% for PLD-based regimen and 82.3% for epirubicin-based regimen. This difference was not significant (p = 0.939). Stage IIIa disease was associated with a shorter DFS in univariate analysis (p = 0.048). In multivariate analysis that controlled for adjuvant treatment, age at diagnosis, stage, HER-2 expression, type of surgery and hormone and radiation therapy, stage IIIa disease (P = 0.023) and lack of hormone therapy (P = 0.024) were each independently associated with shorter DFS. Adverse events were evaluated, and with the exception of hand-foot syndrome, more grade 3 and 4 toxicities occurred in patients who received epirubicin-based regimens than in those given PLD-based regimens. CONCLUSION: For patients with early-stage breast cancer who received PLD-based adjuvant chemotherapy, 5-year DFS was comparable and toxicity was acceptable, yet different from those of patients who received epirubicin-based regimens.

Cancer-related pain: a nationwide survey of patients' treatment modification and satisfaction in Taiwan.

BACKGROUND: We have limited knowledge about cancer patients' pain control satisfaction in outpatient departments in Taiwan and doctors' practice of adjusting analgesics according to their pain status. This survey examined pain management and satisfaction among cancer outpatients with pain and obtained information on their quality of life and treatment management for different pain intensities. METHODS: The Short version of the Brief Pain Inventory was used as the outcome questionnaire. Participants comprised 2075 patients with different cancers and disease statuses at 14 oncological outpatient departments, of which 1051 reported pain within the week prior to testing. The impact of pain management on physical and psychological functioning, and satisfaction with doctors were evaluated. Information about doctors' prescriptions was collected. Logistic regression analyses were conducted to evaluate whether the interference scale performed identically in the different analgesic ladders. RESULTS: Pain was significantly linked to disease status and affected patients' physical and psychiatric functioning. Almost 100% of patients were satisfied with their pain control, but more than 70% of doctors did not change analgesics based on patients' current pain status. The results show that although patients were satisfied with their physicians, treatment of cancer pain was still suboptimal. CONCLUSION: Pain assessment and treatment need to be more thorough and management guidelines should be revised to improve pain control in patients with cancer.

Promotion of metastasis of thyroid cancer cells via NRP-2-mediated induction.

Tumor-node-metastasis is one of the leading causes of morbidity and mortality in thyroid cancer patients. Upregulation of vascular endothelial growth factor-C (VEGF-C) increases the migratory ability of thyroid cancer cells to lymph nodes. Expression of neuropilin-2 (NRP-2), the co-receptor of VEGF-C, has been reported to be correlated with lymph node metastasis in human thyroid cancer. The present study investigated the role of VEGF-C/NRP-2 signaling in the regulation of metastasis of two different types of human thyroid cancer cells. The results indicated that the VEGF-C/NRP-2 axis significantly promoted the metastatic activities of papillary thyroid carcinoma cells through the activation of the mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-regulated kinase and p38 MAPK signaling cascades. However, neither MEK or p38 MAPK inhibitors produced significant inhibition of the migratory activity and invasiveness regulated by the VEGF-C/NRP-2 axis in follicular thyroid carcinoma cells. Finally, VEGF-C/NRP-2-mediated invasion and migration of thyroid cancer cells required the expression of NRP-2. The present results demonstrate that the promotion of metastasis by VEGF-C is mainly due to the upregulation of NRP-2 in thyroid cancer cells, and this metastatic activity regulated by the VEGF-C/NRP-2 axis provides further insight into the process of tumor metastasis.

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2.

Oral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000, and is the fourth leading cause of cancer-associated mortality among men in Taiwan. Cisplatin and 5-fluorouracil (5-FU) are two of the most frequently utilized chemotherapy drugs for the treatment of oral cancer. Although oral cancer patients initially benefit from chemotherapy with these drugs, they may develop resistance to them, which worsens their prognosis and reduces survival rates. It has been reported that increased levels of epidermal growth factor receptor (EGFR) and multidrug resistance-associated protein 2 (MRP2) induce drug resistance in numerous types of human cancer. Therefore, the present study employed lentivirus vector-mediated RNA interference (RNAi) in order to target the genes encoding EGFR and MRP2 in the oral squamous cell carcinoma cell line OC2. It was observed that RNAi-mediated downregulation of EGFR or MRP2 increased the sensitivity to 5-FU and cisplatin in OC2 cells. Downregulation of EGFR resulted in significant suppression of OC2 tumor growth following 5-FU administration. However, simultaneous downregulation of the two genes did not further suppress the tumor growth, indicating that MRP2 does not have a significant role in the chemosensitivity of EGFR-downregulated cells to 5-FU. In contrast, downregulation of MRP2 was demonstrated to significantly enhance the therapeutic effects of cisplatin in EGFR-downregulated OC2 tumors. The observation that the expression of MRP2 was positively correlated with the level of cisplatin resistance in cells suggests that RNAi-mediated downregulation of MRP2 may be applicable as a therapeutic approach toward reversing MRP2-dependent cisplatin resistance in oral cancer.

Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells.

Reversine, an A3 adenosine receptor antagonist, has been shown to induce differentiated myogenic-lineage committed cells to become multipotent mesenchymal progenitor cells. We and others have reported that reversine has an effect on human tumor suppression. This study revealed anti-tumor effects of reversine on proliferation, apoptosis and autophagy induction in human non-small cell lung cancer cells. Treatment of these cells with reversine suppressed cell growth in a time- and dosage-dependent manner. Moreover, polyploidy occurred after reversine treatment. In addition, caspase-dependent apoptosis and activation of autophagy by reversine in a dosage-dependent manner were also observed. We demonstrated in this study that reversine contributes to growth inhibition, apoptosis and autophagy induction in human lung cancer cells. Therefore, reversine used as a potential therapeutic agent for human lung cancer is worthy of further investigation.

Hinokitiol inhibits vasculogenic mimicry activity of breast cancer stem/progenitor cells through proteasome-mediated degradation of epidermal growth factor receptor.

Hinokitiol, alternatively known as ß-thujaplicin, is a tropolone-associated natural compound with antimicrobial, anti-inflammatory and antitumor activity. Breast cancer stem/progenitor cells (BCSCs) are a subpopulation of breast cancer cells associated with tumor initiation, chemoresistance and metastatic behavior, and may be enriched by mammosphere cultivation. Previous studies have demonstrated that BCSCs exhibit vasculogenic mimicry (VM) activity via the epidermal growth factor receptor (EGFR) signaling pathway. The present study investigated the anti-VM activity of hinokitiol in BCSCs. At a concentration below the half maximal inhibitory concentration, hinokitiol inhibited VM formation of mammosphere cells derived from two human breast cancer cell lines. Hinokitiol was additionally indicated to downregulate EGFR protein expression in mammosphere-forming BCSCs without affecting the expression of messenger RNA. The protein stability of EGFR in BCSCs was also decreased by hinokitiol. The EGFR protein expression and VM formation capability of hinokitiol-treated BCSCs were restored by co-treatment with MG132, a proteasome inhibitor. In conclusion, the present study indicated that hinokitiol may inhibit the VM activity of BCSCs through stimulating proteasome-mediated EGFR degradation. Hinokitiol may act as an anti-VM agent, and may be useful for the development of novel breast cancer therapeutic agents.

Pegylated Liposomal Doxorubicin as Adjuvant Therapy for Stage I-III Operable Breast Cancer.

BACKGROUND: Conventional anthracyclines play an essential role for the treatment of breast cancer and have potent cytotoxic activity, but are associated with severe toxicity. In metastatic breast cancer, pegylated liposomal doxorubicin (PLD) is a formulation with efficacy similar to conventional doxorubicin but with reduced toxicity. This multicenter study evaluated the efficacy and safety of PLD-based adjuvant chemotherapy for women with stage I-III operable breast cancer. PATIENTS AND METHODS: One hundred and eighty women with stage I-III breast cancer who received PLD-based adjuvant chemotherapy at six different Institutions in Taiwan from February 2002 to March 2008 were included and followed-up until April 2015. Treatment efficacy was determined by disease-free survival (DFS) rate and safety was evaluated by adverse events. RESULTS: The 5- and 10-year DFS rates were 76.3 and 72.6%, respectively. Univariate analysis revealed that tumor size >5 cm (p=0.045; hazard ratio=3.31) and stage III (hazard ratio=3.54; p=0.019) were each associated with shorter DFS. Only stage III (hazard ratio=5.60; p=0.018) retained statistical significance with regard to DFS in the multivariate analysis. Grade 3/4 hematological toxicity was neutropenia (n=13; 7.2%). The women receiving PLD had low-grade 3 or 4 nausea/vomiting, mucositis, and alopecia. Grade 3 hand-foot syndrome occurred in three patients (1.7%). CONCLUSION: PLD could be considered an effective and safe alternative to conventional anthracyclines in the treatment of stage I-III operable breast cancer.