Deforestation for oil palm increases microclimate suitability for the development of the disease vector Aedes albopictus.

A major trade-off of land-use change is the potential for increased risk of infectious diseases, a.o. through impacting disease vector life-cycles. Evaluating the public health implications of land-use conversions requires spatially detailed modelling linking land-use to vector ecology. Here, we estimate the impact of deforestation for oil palm cultivation on the number of life-cycle completions of Aedes albopictus via its impact on local microclimates. We apply a recently developed mechanistic phenology model to a fine-scaled (50-m resolution) microclimate dataset that includes daily temperature, rainfall and evaporation. Results of this combined model indicate that the conversion from lowland rainforest to plantations increases suitability for A. albopictus development by 10.8%, moderated to 4.7% with oil palm growth to maturity. Deforestation followed by typical plantation planting-maturation-clearance-replanting cycles is predicted to create pulses of high development suitability. Our results highlight the need to explore sustainable land-use scenarios that resolve conflicts between agricultural and human health objectives.

What factor within the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria is most strongly correlated with trauma induced DIC? A retrospective study using thromboelastometry in a single center in Japan.

PURPOSE: The diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) is able to diagnose DIC accurately and promptly. The aim of this retrospective study is to evaluate the degree of association between each parameter of JAAM DIC criteria and the diagnosis of trauma induced DIC (T-DIC) utilizing thromboelastometry (ROTEM). METHODS: Trauma patients transported to our hospital with ROTEM performed in the emergency department between January 2013 and December 2015 were enrolled in this study. We evaluated (1) the characteristics of T-DIC, (2) the relationships between T-DIC and each parameter of the JAAM DIC criteria and (3) the diagnostic accuracies of each parameter for T-DIC by statistical measurement. RESULTS: All 72 patients (21 T-DIC and 51 control) were included in primary analysis. T-DIC was significantly related to younger age, more severe trauma scores, more cases of massive transfusions, and remarkable coagulation abnormality detected by standard coagulation tests. In the cases of T-DIC, ROTEM showed longer clotting time, lower acceleration, lower clot firmness, and inhibited fibrinolysis in EXTEM/INTEM. Within the JAAM DIC score, PT-INR ≥1.2 was the most accurate factor for T-DIC diagnosis; sensitivity 60.0%, specificity 100.0%, and accuracy 88.7%. PT-INR ≥1.2 was statistically correlated with the JAAM DIC score (p < 0.001, r = 0.709). The univariate analysis based on 1.2 of PT-INR indicated statistical differences in most categories of ROTEM, which is similar to analysis performed for the presence and absence of T-DIC. CONCLUSIONS: Among JAAM DIC criteria, the PT-INR ≥1.2 was the most accurate factor for both the diagnosis of T-DIC and the evaluation of its severity.

Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium.

Chlorinated benz[a]anthracenes (Cl-BaA) are halogenated aromatic compounds (typified by dioxins) found in the environment at relatively high concentrations. Fischer 344 rats were intragastrically administered 0, 1, or 10 mg of Cl-BaA or its parent compound benz[a]anthracene (BaA) per kg of body weight for 14 consecutive days. Both chemicals at 10 mg/kg/day inhibited the gain in body weight, and consequent increase in relative liver weight. Hepatic gene expression of cytochrome P450 (CYP) 1A1, 1A2, and 1B1 was significantly stimulated by administration of BaA (10 mg/kg/day) compared with the control. After administration of Cl-BaA, only the CYP1A2 gene was significantly induced, even at the lower dosage; CYP1A1 and 1B1 mRNA levels remained unchanged in Cl-BaA-treated rats compared with controls. To elucidate the role of such Cl-BaA exposure and induced CYPs at toxicity onset, we investigated the mutagenicity of BaA and Cl-BaA using Salmonella typhimurium TA98 and TA100. BaA and Cl-BaA at 10 µg/plate produced positive results in both strains in the presence of rat S-9. Incubation of Cl-BaA with recombinant rat CYP1A2 produced a significantly higher number of revertant colonies in TA98 and TA100 than in controls, but no such change was observed for BaA. In conclusion, BaA changes its own physiological and toxicological actions by its chlorination; (1) daily exposure to Cl-BaA selectively induces hepatic CYP1A2 in rats and (2) Cl-BaA induces frameshift mutations in the presence of CYP1A2, although BaA does not exert mutagenicity. This indicates that CYP1A2 may metabolize Cl-BaA to active forms.

Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters.

3,4-Methylendioxymethamphetamine (MDMA) has both stimulatory and hallucinogenic properties which make its psychoactive effects unique and different from those of typical psychostimulant and hallucinogenic agents. The present study investigated the effects of MDMA on extracellular dopamine (DA(ex)) and serotonin (5-HT(ex)) levels in the striatum and prefrontal cortex (PFC) using in vivo microdialysis techniques in mice lacking DA transporters (DAT) and/or 5-HT transporters (SERT). subcutaneous injection of MDMA (3, 10 mg/kg) significantly increased striatal DA(ex) in wild-type mice, SERT knockout mice, and DAT knockout mice, but not in DAT/SERT double-knockout mice. The MDMA-induced increase in striatal DA(ex) in SERT knockout mice was significantly less than in wildtype mice. In the PFC, MDMA dose-dependently increased DA(ex) levels in wildtype, DAT knockout, SERT knockout and DAT/SERT double-knockout mice to a similar extent. In contrast, MDMA markedly increased 5-HT(ex) in wildtype and DAT knockout mice and slightly increased 5-HT(ex) in SERT-KO and DAT/SERT double-knockout mice. The results confirm that MDMA acts at both DAT and SERT and increases DA(ex) and 5-HT(ex).

Enhanced Hyperthermia Induced by MDMA in Parkin Knockout Mice.

MDMA (3,4-methylenedioxymethamphetamine) is reportedly severely toxic to both dopamine (DA) and serotonin neurons. MDMA significantly reduces the number of DA neurons in the substantia nigra, but not in the nucleus accumbens, indicating that MDMA causes selective destruction of DA neurons in the nigrostriatal pathway, sparing the mesolimbic pathway. Parkinson's disease (PD) is a neurodegenerative disorder of multifactorial origin. The pathological hallmark of PD is the degeneration of DA neurons in the nigrostriatal pathway. Mutations in the parkin gene are frequently observed in autosomal recessive parkinsonism in humans. Parkin is hypothesized to protect against neurotoxic insult, and we attempted to clarify the role of parkin in MDMA-induced hyperthermia, one of the causal factors of neuronal damage, using parkin knockout mice. Body temperature was measured rectally before and 15, 30, 45, and 60 min after intraperitoneal injection of MDMA (30 mg/kg) at an ambient temperature of 22 ± 2°C. Significantly enhanced hyper-thermia after MDMA injection was observed in heterozygous and homozygous parkin knockout mice compared with wildtype mice, suggesting that parkin plays a protective role in MDMA neurotoxicity.

[Off-pump coronary artery bypass grafting for angina pectoris with coronary artery aneurysm due to kawasaki disease: report of a case].

We report a 27-year-old woman who underwent off-pump coronary artery bypass grafting (OPCAB) for angina pectoris with coronary artery aneurysm due to Kawasaki disease. At the age of 3, she was diagnosed as Kawasaki disease with coronary artery aneurysms in the right coronary artery and the left anterior descending artery. She was medically followed-up since then Because an enlarged aneurysm and a stenotic lesion were recognized in the right coronary artery, operation was indicated. In operation, the right coronary artery was ligated at the inflow and the outflow of the aneurysm. OPCAB was also conducted with the right internal thoracic artery anastomosed to the right coronary artery. Postoperative course was uneventful, and she was discharged at the day 5 after operation. Revascularization using arterial grafts, especially the internal thoracic arteries, may be the choice for young patients to expect a good patency rate in the long-term.

[Off-pump coronary artery bypass grafting as standard operation; surgical strategies and results].

We report the clinical results of 799 cases of isolated coronary artery bypass grafting (CABG) performed during the recent 5 years. We performed off-pump CABG (OPCAB) as standard operation, in which arterial grafts were mainly used. The mean number of distal anastomoses was 3.6 +/- 1.4 per patient Four hundred and fifty-five cases (57.0%) were done only with arterial grafts. Bilateral internal thoracic arteries were used in 326 cases. The mean number of saphenous vein grafts was 1.6 +/- 0.8 per patient. Continuous hemodiafiltraion (CHDF) was performed in 22 cases (2.8%) postoperatively. Among the OPCAB cases, 10 cases (1.3%) were converted to on-pump CABG. There were 7 cases (0.9%) of hospital death. The mean length of postoperative hospital stay was 10.2 +/- 5.3 days. The ratio of the patients with left main trunk disease and that of the patients who required postoperative CHDF increased year by year. The mean length of postoperative hospital stay decreased every year, and the reduced length was 2.7 days in the 5 years (8.7+/- 3.6 days in 2007). It is expected that patients who have severe calcified lesions or who are on hemodialysis may increase in the near future. In such cases, CABG rather than percutaneous catheter intervention may be suitable for revascularization. Therefore, not only appropriate choice of treatment strategies, but also accurate surgical techniques may become more importance.

Constitutive IL-8 expression in cancer cells is associated with mutation of p53.

We previously reported that most cancer cell lines constitutively express various cytokines including IL-8. But how IL-8 gene expression is regulated in cancer cells is still unclear. p53 tumor suppressor gene plays an important role in the regulation of transcription and is mutated in cancer cell lines. We investigated whether p53 status affects the constitutive expression of IL-8 in human cancer cells. SUIT-2 and RERF-LCOK cancer cells constitutively produced high levels of IL-8 in culture medium. Both cell lines were shown to carry a p53 mutation, and constitutive NF-kappaB transcriptional activity. To analyze whether p53 status mediates IL-8 expression, the effect of wild-type p53 (wt-p53) gene transfer on activation of NF-kappaB was determined in both cell lines. ELISA showed that the IL-8 concentration in medium decreased dose dependently by transient expression of wt-p53. Western-blot analysis showed no marked change in NF-kappaB protein levels in cell nuclei. EMSA showed no repression of NF-kappaB binding activity after transient expression of wt-p53. In contrast, luciferase reporter studies indicated that transcriptional activity of NF-kappaB is suppressed by transfection of wt-p53. These results show that wt-p53 gene transfer inhibits IL-8 production and NF-kappaB transcription activity in cancer cells and suggest that constitutive IL-8 production in cancer cells is associated with mutation of p53.

Mechanisms of taxotere-related drug resistance in pancreatic carcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is generally refractory to most chemotherapeutic agents, including docetaxel (Taxotere; TXT). Specific mechanisms for TXT-related drug resistance in PAC have not been defined. The hypothesis of this study was that PAC resistance to TXT is primarily related to P-glycoprotein (P-gp), the expression product of multiple drug resistance (MDR)-1, as opposed to lung resistance protein (LRP) or multidrug resistance protein (MRP). MATERIALS AND METHODS: The sensitivity of the PAC cell line SUIT-2 and its sublines to TXT, doxorubicin (DOX) and 5-fluorouracil (5-FU) was evaluated with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. MDR1 (P-gp), MRP, LRP, and beta-tubulin isotype gene expressions were detected at the messenger RNA level by reverse transcription-polymerase chain reaction (RT-PCR). Verapamil and indomethacin (IMC) were used to test the functionality of P-gp and MRP, respectively. RESULTS: The SUIT-2 subline S-020 and the TXT-selected SUIT-2 cell line S2/TXT were significantly resistant to TXT. Both showed cross-resistance to DOX but no resistance to 5-FU. RT-PCR demonstrated strong expression of P-gp in S-020 and S2/TXT and weaker or no expression in other cells lines. MRP and LRP expression was found in most of these cell lines but had no relationship to the TXT resistance. TXT resistance in S2-020 and S2/TXT could be reversed by verapamil but not by IMC. Levels of beta-tubulin isotype II and III were increased in S2/TXT compared with S-020 and SUIT-2. CONCLUSIONS: Intrinsic and acquired TXT resistance is primarily mediated by P-gp, but not by MRP or LRP, and is markedly reversed by the P-gp modulator verapamil. Hence future related studies should focus on the use of agents that block the transporter action of P-gp.

Synchronous double cancer of the stomach and rectum with situs inversus totalis and polysplenia syndrome.

Situs solitus refers to the normal arrangement of body organs. Situs inversus totalis is a complete mirror image or reverse isomeric form of the thoracic and abdominal viscera. Any arrangement of organs between these two extremes is designated by heterotaxia. Several patterns of vascular and visceral abnormalities are associated with heterotaxia, and two loosely defined syndromes of splenic anomalies (asplenia and polysplenia) are most common. We present the case of a 71-year-old woman with situs inversus totalis and polysplenia syndrome who developed synchronous double cancer originating from the stomach and rectum. Abdominal manifestations were situs inversus totalis combined with multiple lobulated spleen, azygous continuation of the interrupted inferior vena cava, direct drainage of hepatic vein to left atrium, preduodenal portal vein, short pancreas, incomplete rotation of the colon, and malrotation of the intestine. Histologically, gastric cancer was diagnosed as papillary adenocarcinoma and rectal cancer, as moderately differentiated adenocarcinoma. The patient was successfully treated with total gastrectomy for gastric cancer and low-anterior resection of the rectum for rectal cancer.

PACT, a double-stranded RNA binding protein acts as a positive regulator for type I interferon gene induced by Newcastle disease virus.

Virus infection triggers innate responses to host cells including production of type I interferon (IFN). Since IFN production is also induced by treatment with poly(I:C), viral double-stranded (ds) RNA has been postulated to play a direct role in the process. In the present study, we investigated the effect of dsRNA binding proteins on virus-induced activation of the IFN-beta gene. We found that PACT, originally identified as protein activator for dsRNA-dependent protein kinase (PKR) and implicated in the regulation of translation, augmented IFN-beta gene activation induced by Newcastle disease virus. Concomitantly with the augmented activity of IFN-beta enhancer, increased activity of NF-kappaB and IRF-3 and IRF-7 was observed. For the observed effect, the dsRNA-binding activity of PACT was essential. We identified residues of PACT that interact with a presumptive target molecule to exert its function. Furthermore, PACT colocalized with viral replication complex in the infected cells. Thus the observed effect of PACT is novel and PACT is involved in the regulation of viral replication and results in a marked increase of cellular IFN-beta gene expression.

Invasiveness and MMP expression in pancreatic carcinoma.

BACKGROUND: Previous investigations have suggested that expression of matrix metalloproteinases (MMPs) may be related to increased invasiveness of various tumors. This study evaluated a possible relation between pancreatic tumor cell invasiveness and MMPs. METHODS: A Matrigel invasion assay was performed with pancreatic tumor cell line SUIT-2 and its sublines S2-007, S2-013, S2-020, and S2-028. The degree of invasiveness of stimulated and unstimulated cell lines was correlated with MMP gene expression measured by RT-PCR and MMP protein product measured by gelatin zymography. Cell lines were stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), concanavalin (Con-A), and polymerized collagen type I gel (Vitrogen). RESULTS: For SUIT-2, S2-007, S2-013, S2-020, and S2-028, 3.2, 1.0, 4.1, 6.4, and 0.4%, respectively, of the cells invaded the Matrigel membrane. TPA, Con-A, and Vitrogen resulted in the up-regulation of MMP-2 in S2-020. TPA and Vitrogen resulted in up-regulation of MMP-9 in each of the cell lines, while Con-A could up-regulate MMP-9 expression only in SUIT-2. There was no constitutive expression of either MMP-2 or MMP-9 in SUIT-2 or its sublines. There was a positive relationship between Matrigel invasiveness and up-regulation of MMP-2 and MMP-9 expression. CONCLUSION: These data suggest that, while MMP-2 and MMP-9 are not constitutively expressed in pancreatic carcinoma cell lines, they may be up-regulated by TPA, Con-A, and Vitrogen. Since MMP-2 and MMP-9 expression correlated with degree of tumor cell invasiveness, the ability to up-regulate MMP-2 and MMP-9 expression may play a role in facilitating pancreatic tumor cell invasion.

Induction of IRF-3/-7 kinase and NF-kappaB in response to double-stranded RNA and virus infection: common and unique pathways.

BACKGROUND: Infection by virus or treatment with double-stranded RNA (dsRNA) results in the activation of transcription factors including IRF-3, IRF-7 and a pleiotropic regulator NF-kappaB by specific phosphorylation. These factors are important in triggering a cascade of antiviral responses. A protein kinase that is yet to be identified is responsible for the activation of these factors and plays a key role in the responses. RESULTS: The signal cascade was analysed using sensitive assays for the activation of IRF-3 and NF-kappaB, and various inhibitors. We found that the activation of IRF-3 and NF-kappaB by dsRNA or virus involves a process that is sensitive to Geldanamycin. Although the induction of NF-kappaB by dsRNA/virus and TNF-alpha involves common downstream pathways including IKK activation, the upstream, Geldanamycin-sensitive process was unique to the dsRNA/virus-induced signal. By an in vitro assay using cell extract, we found an inducible protein kinase activity with physiological specificity of IRF-3 phosphorylation. Furthermore, the same extract specifically phosphorylated IRF-7 in a similar manner. CONCLUSIONS: Double-stranded RNA or virus triggers a specific signal cascade that results in the activation of the IRF-3/-7 kinase we detected, which corresponds to the long-sought signalling machinery that is responsible for triggering the early phase of innate response. The signal branches to a common NF-kappaB activation cascade, thus resulting in the activation of a set of critical transcription factors for the response.

Newly established assay method for 25-hydroxyvitamin D3 24-hydroxylase revealed much lower Km for 25-hydroxyvitamin D3 than for 1alpha,25-dihydroxyvitamin D3.

An accurate assay method of 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) was established. Kidney mitochondria prepared from vitamin D-replete rats were treated with polyoxyethylenesorbitan monolaurate. The solubilized suspension was ultracentrifuged at 100,000g for 60 minutes and an aliquot of the supernatant was incubated under the saturating concentrations of substrate NADPH and the mitochondrial-type electron transferring proteins, adrenodoxin and NADPH-adrenodoxin reductase. Products were analyzed by high-performance liquid chromatography (HPLC) monitoring effluents at a wavelength of 265 nm. The maximal velocity of the enzyme in vitamin D-replete rats was 400 pmol/minute per mg of protein, which was considerably higher than those reported by previous authors who used intact kidney mitochondria as the enzyme source. In applying the new assay method, an interesting property was found; Michaelis constant of 24-hydroxylase for 25-hydroxyvitamin D3 [25(OH)D3] was 0.6 microM, which was 35-fold lower than that for 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] which was 20.9 microM. This fact indicates that affinity of the enzyme to 25(OH)D3 is 35-fold higher than that to 1alpha,25(OH)2D3. These data suggest that 25(OH)D3 is the preferred substrate to 1alpha,25(OH)2D3.

Taxotere resistance in SUIT Taxotere resistance in pancreatic carcinoma cell line SUIT 2 and its sublines.

AIM: To investigate the specific mechanisms of intrinsic and acquired resistance to taxotere (TXT) in pancreatic adenocarcinoma (PAC). METHODS: MTT assay was used to detect the sensitivity of PAC cell line SUIT-2 and its sublines (S-007, S-013, S-020, S-028 and TXT selected SUIT-2 cell line, S2/TXT) to TXT. Mdr1 (P-gp), multidrug resistance associated protein (MRP), lung resistance protein (LRP) and beta-tubulin isotype gene expressions were detected by RT-PCR. The functionality of P-gp and MRP was tested using their specific blocker verapamil (Ver) and indomethacin (IMC), respectively. The transporter activity of P-gp was also confirmed by Rhodamine 123 accumulation assay. RESULTS: S-020 and S2/TXT were found to be significantly resistant to TXT(19 and 9.5-fold to their parental cell line SUIT-2, respectively). RT-PCR demonstrated strong expression of Mdr1 in these two cell lines, but weaker expression or no expression in other cells lines. MRP and LRP expressions were found in most of these cell lines. The TXT-resistance in S2-020 and S2/TXT could be reversed almost completely by Ver, but not by IMC. Flow cytometry showed that Ver increased the accumulation of Rhodamine-123 in these two cell lines. Compared with S-020 and SUIT-2, the levels of beta-tubulin isotype II, III expressions in S-2/TXT were increased remarkably. CONCLUSION: The both intrinsic and acquired TXT-related drug resistance in these PAC cell lines is mainly mediated by P-gp, but had no relationship to MRP and LRP expressions. The increases of beta-tubulin isotype II, III might be collateral changes that occur when the SUIT-2 cells are treated with TXT.

Self-assisted tandem Michael-aldol reactions of alpha,beta-unsaturated ketones with aldehydes.

The tandem Michael-aldol reaction of 1-[2-(methylsulfanyl)-phenyl]prop-2-en-1-one (1) or the seleno congener 4 with p-nitrobenzaldehyde in the presence of BF3.Et2O gave the Baylis-Hillman adduct 2 or 5 and onium salt 3 or 6, respectively, and selenochromanone 7 from 4.

Elastase activity enhances the adhesion of neutrophil and cancer cells to vascular endothelial cells.

BACKGROUND: Elastase activity in cancer cells has been reported to promote their metastasis. Hence, we analyzed the influence of elastase activity of cancer cells on their responsive adhesion to vascular endothelial cells. MATERIALS AND METHODS: Human pancreatic (S2-007, S2-013, S2-020, S2-028) and colonic (COLO205) cancer cell lines were used. S2-007, S2-013, and S2-020 possess high elastase activity, whereas S2-028 and COLO205 have low elastase activity. Adhesive reactions of these cancer cells and neutrophils to TNFalpha-activated HUVEC were analyzed. Bound cells onto HUVEC were counted after incubation for 10 min. The effects of suppression of elastase activity by ZD8321, a potent elastase inhibitor, and supplementation of human neutrophil elastase (NE) on the adhesive reactions were also analyzed. In addition, E-selectin expression on HUVEC and concentrations of soluble E-selectin in the medium were measured. RESULTS: Adhesion of cells with high intracellular elastase activity to TNFalpha-activated HUVEC was suppressed by ZD8321. On the other hand, adhesion of cells with low elastase activity was enhanced by exogenous NE. Expression of E-selectin, a key molecule in leukocyte-endothelial cell interaction, on HUVEC was increased by NE. Soluble E-selectin concentration in the medium increased after the adhesive reaction between neutrophils and HUVEC. This increase was thought to be due to the shedding of cell surface E-selectin. Such responses were inhibited by ZD8321. CONCLUSION: Elastase activity has a biological function of stimulating both the E-selectin expression on HUVEC and the resultant adhesive reaction of cancer cells with them. Inhibition of elastase activity is a potent strategy for controlling cancer metastasis.

Tumor necrosis factor alpha acts on cultured human vascular endothelial cells to increase the adhesion of pancreatic cancer cells.

We studied the effect of tumor necrosis factor alpha (TNFalpha), one of the major inflammatory cytokines, on the adhesive reaction of pancreatic cancer cells to human umbilical vein endothelial cells (HUVECs) and on the hepatic metastasis of cancer cells in vivo. After TNFalpha stimulation, the expression of E-selectin, an adhesion molecule to neutrophils on HUVECs, increased. In addition, the adhesion of pancreatic cancer cells to HUVECs increased after TNFalpha stimulation, as was observed with neutrophils. The TNFalpha-induced adhesive response depended on the extent of sialyl Lewis(a) expression on cancer cells. The hepatic metastasis in vivo was often observed when cancer cells expressing a high amount of sialyl Lewis(a) were inoculated intrasplenically after increase in plasma TNFalpha concentration by lipopolysaccharide administration. Because sialyl Lewis(a) on cancer cells is a ligand for E-selectin on HUVECs, as sialyl Lewis(x) on neutrophils, TNFalpha upregulated the adhesive interaction between sialyl Lewis(a) on cancer cells and E-selectin on HUVECs. These results suggest that production of TNFalpha after surgical trauma may stimulate the hematogenic metastasis of cancer cells with a high sialyl Lewis(a) expression.

Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells.

We characterized anticancer effects of opioid analgesics that are clinically used for cancer patients for pain relief. Treatment with 100 microM buprenorphine, a representative analgesic, induced cell death of human carcinomas, such as A549 (squamous epithelial cell of lung cancer), MCF-7 (breast cancer) and N417 (small cell of lung cancer), but not in KATO III (gastric cancer) cells as evaluated by alamar blue assay. Among 18 clinically utilized and related analgesics, buprenorphine and loperamide showed potent inhibition of cell viability. However, these anti-cancer effects were not affected by opioid receptor antagonists nor by pertussis toxin. Buprenorphine-induced cell death occurred as early as 1 h after the addition, and its T1/2 of cell viability inhibition was 3 h. The cell death manifested the characteristics of apoptosis, such as DNA-laddering and nuclear fragmentation, which were sensitive to a caspase inhibitor, Z-Asp-CH2-DCB. The nuclear fragmentation was independent of cell cycle phase specificity. The activity of caspase-3-like protease which is known to be closely related to apoptotic DNA laddering was markedly enhanced by buprenorphine. However, the inhibition of cell viability by buprenorphine was not affected by the caspase inhibitor. These findings suggest that some opioid analgesics induce typical apoptotic features sensitive to the caspase inhibitor, while also inhibition of cell viability insensitive to the inhibitor.