Lysine specific demethylase 1 (LSD1), a transcriptional corepressor or coactivator that serves as a demethylase of histone 3 lysine 4 and 9, has become a potential therapeutic target for cancer therapy. LSD1 mediates many cellular signaling pathways and regulates cancer cell proliferation, invasion, migration, and differentiation. Recent research has focused on the exploration of its pharmacological inhibitors. Natural products are a major source of compounds with abundant scaffold diversity and structural complexity, which have made a major contribution to drug discovery, particularly anticancer agents. In this review, we briefly highlight recent advances in natural LSD1 inhibitors over the past decade. We present a comprehensive review on their discovery and identification process, natural plant sources, chemical structures, anticancer effects, and structure-activity relationships, and finally provide our perspective on the development of novel natural LSD1 inhibitors for cancer therapy.
Antineoplastic Agents/therapeutic use* ; Enzyme Inhibitors/therapeutic use* ; Histone Demethylases/metabolism* ; Humans ; Lysine/therapeutic use* ; Neoplasms/drug therapy*

BACKGROUND/AIMS: Terlipressin and octreotide had been used to control acute variceal bleeding and to prevent early rebleeding after endoscopic hemostasis. We compared the efficacy and safety of terlipressin and octreotide combined with endoscopic variceal ligation (EVL) for the treatment of acute esophageal variceal bleeding and we evaluated their clinical significance as related to rebleeding. METHODS: The eighty eight cirrhotic patients were randomized to the terlipressin group (n=43; 2 mg i.v. initially and 1 mg i.v. at every 4 hours for 3 days) or the octreotide group (n=45; continuous infusion of 25 microgram/h for 5 days) combined with EVL for the treatment of acute esophageal variceal bleeding. RESULTS: The initial hemostasis rates were 98% (42/43 cases) in the terlipressin group and 96% (43/45 cases) in the octreotide group. The 5-day and 42-day rebleeding rates were 12% (5/43 cases) and 28% (12/43 cases), respectively, in the terlipressin group and 9% (4/45 cases) and 24% (11/45 cases), respectively, in the octreotide group. No significant difference was demonstrated between the terlipressin and octreotide groups. The mortality at 42 days was similar in both group, but a high mortality rate (48%) was shown to be related to 42-day rebleeding. The risk factors related to 42-day rebleeding were Child-Pugh class C (aOR=30.2, 95% CI=7.7-117.9), ascites above grade II (aOR=6.6, 95% CI=2.2-19.2) and advanced hepatocellular carcinoma (aOR=4.6, 95% CI=1.1-18.9). CONCLUSIONS: Comparing terlipressin and octreotide combined with EVL showed them to be equally safe and effective therapeutic agents in patients with acute esophageal variceal bleeding. The high risk factors related to early rebleeding were poor liver function and advanced hepatocellular carcinoma.
Acute Disease ; Aged ; Esophageal and Gastric Varices/drug therapy/surgery/*therapy ; Female ; Gastrointestinal Hemorrhage/drug therapy/surgery/*therapy ; Humans ; Liver Cirrhosis/drug therapy/surgery/*therapy ; Lysine Vasopressin/*analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Octreotide/*therapeutic use ; Vasoconstrictor Agents/*therapeutic use

With recent progress in treatment modalities, mortality from upper gastrointestinal (UGI) bleeding has decreased appreciably. The aim of this study was to establish how UGI bleeds are managed in Korean patients with cirrhosis and to evaluate treatment outcomes. A total of 479 episodes of acute UGI bleeding in 464 patients with cirrhosis were included during a six-month period at nine tertiary medical centers. Treatment outcomes were assessed by failure to control bleeding, rebleeding and mortality. The source of bleeding was esophagogastric varices in 77.7% of patients, nonvariceal lesions in 15.9%, and undefined in 6.5%. For control of bleeding, endoscopic and pharmacologic treatments were used in 74.7% and 81.9% of patients, respectively. Variceal ligation was a major technique for endoscopic treatment (90%), and terlipressin and somatostatin were the main pharmacologic agents used (96.4%). Initial hemostasis was achieved in 86.8% of cases, but rebleeding occurred in 3.8% and 16.8% of cases within five days and six weeks of hemorrhage, respectively. Five-day and six-week mortality were 11.3% and 25.9%, respectively. Survival of patients with variceal bleeding seems to be remarkably improved than previous reports, which may suggest the advances in hemostatic methods for control of variceal hemorrhage..
Adult ; Aged ; Cohort Studies ; Female ; Gastrointestinal Hemorrhage/mortality/*therapy ; Hemostatic Techniques ; Humans ; Infection/epidemiology ; Liver Cirrhosis/*complications ; Lysine Vasopressin/analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Treatment Outcome

Hepatorenal syndrome is a severe complication of cirrhosis, leading to death in more than 90% of cases in the absence of liver transplantation. Several treatments have been attempted as a bridge to liver transplantation. Among such treatments, terlipressin is a nonselective V1 vasopressin agonist. When comparing with ornipressin, it is known to have a similar vasoconstricting potency, but much less ischemic complication. We report a case of gangrene on toes and necrosis on the infusion site of left hand which developed after the use of terlipressin due to hepatorenal syndrome in a 41-year-old-man with liver cirrhosis. Ischemic complication of terlipressin is rare and there has been no case report in Korea. Although it is rare, we must pay attention to the peripheral ischemic complication of terlipressin.
Adult ; Hand/*blood supply ; Hepatorenal Syndrome/drug therapy ; Humans ; Ischemia/*chemically induced ; Lysine Vasopressin/adverse effects/*analogs & derivatives/therapeutic use ; Male ; Toes/*blood supply ; Vasoconstrictor Agents/*adverse effects/therapeutic use

Terlipressin is a synthetic analogue of vasopressin, which has been used in the treatment of acute variceal hemorrhage. In contrast to vasopressin, terlipressin can be administered as intermittent injections instead of continuous intravenous infusion. Thus, it has a less adverse reaction than vasopressin. We report a case of ischemic skin complication in a cirrhotic patient treated with terlipressin. A 71-year-old man with liver cirrhosis was admitted because of hematemesis and melena. He was commenced on terlipressin at a dose 1 mg every 6 hours for the treatment of varicieal bleeding. After 36 hours of treatment, skin blistering and ecchymosis was noted on the skin of his upper thigh, scrotal area and trunk. We found that terlipressin was a possible cause of ischemic skin complication based on the skin biopsy finding. Terlipressin may induce a complication of the ischemic event. In spite of rarity, special attention needs to paid on the peripheral ischemic complication of terlipressin.
Aged ; Fatal Outcome ; Hematemesis/diagnosis ; Hemorrhage/drug therapy ; Humans ; Ischemia/*chemically induced/*pathology ; Liver Cirrhosis/*complications ; Lysine Vasopressin/administration & dosage/adverse effects/*analogs & derivatives/therapeutic use ; Male ; Melena/diagnosis ; Necrosis ; Skin/*blood supply/drug effects/*pathology ; Vasoconstrictor Agents/administration & dosage/*adverse effects/therapeutic use

BACKGROUNDParaquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ mainly accumulates in the lung, and the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. The aim of this study was to evaluate whether lysine acetylsalicylate (LAS) could protect the lung from the damage of PQ poisoning and to study the mechanisms of protection.

METHODSA model of PQ poisoning was established in 75 Sprague-Dawley rats by intragastric administration of 50 mg/kg PQ, followed by treatment with 200 mg/kg of LAS. The rats were randomly divided into sham, PQ, and PQ + LAS groups, with 25 in each group. We assessed and compared the malonaldehyde (MDA) content, superoxide dismutase activity (SOD), glutathion peroxidase (GSH-Px), and catalase (CAT) in serum and lung and the hydroxyproline (HYP) content, pathological changes, apoptosis and expression of Bcl-2/Bax protein in lung of rats on days 1, 3, 7, 14 and 21 after PQ poisoning and LAS treatment.

RESULTSCompared to the PQ group rats, early treatment with LAS reduced the MDA and HYP contents, and increased the SOD, GSH-Px, and CAT activities in the serum and lung on days 1, 3, 7, 14, and 21 after PQ poisoning (all P < 0.05). After early LAS treatment, the apoptotic rate and Bax expression of lung decreased, the Bcl-2 expression increased, and the Bcl-2/Bax ratio increased, compared to the PQ group rats. Furthermore, the pathological results of lungs revealed that after LAS treatment, early manifestations of PQ poisoning, such as hemorrhage, edema and inflammatory-cell infiltration, were improved to some degree, and collagen fibers in the pulmonary interstitium were also obviously reduced.

CONCLUSIONIn this rat model of PQ poisoning, LAS effectively ameliorated the lung injury induced by PQ, possibly through antioxidation, anti-fibrosis, anti-apoptosis, and anticoagulation.

Animals ; Antioxidants ; metabolism ; Aspirin ; analogs & derivatives ; standards ; therapeutic use ; Catalase ; metabolism ; Glutathione Peroxidase ; metabolism ; Lung ; drug effects ; metabolism ; Lung Injury ; chemically induced ; drug therapy ; metabolism ; Lysine ; analogs & derivatives ; standards ; therapeutic use ; Male ; Malondialdehyde ; metabolism ; Paraquat ; toxicity ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism

BACKGROUND/AIMS: Terlipressin and somatostatin decrease portal venous pressure and they are used for the treatment of variceal bleeding. However, only a few studies have compared the efficacy of these drugs in combination with other procedures for hemostasis. Therefore, we performed a prospective study to compare the efficacy of terlipressin and somatostatin for controlling acute variceal bleeding when used in combination with other procedures for hemostasis. METHODS: A total of 98 patients, who presented with variceal bleeding from September 2003 to May 2005, were randomly divided into the somatostatin group or terlipressin group. We compared the 5-day failure rate (defined as failure to control bleeding, rebleeding or death within 5 days of admission) and the 6-week mortality. The prognostic factors for 5-day failure and 6-week mortality were also evaluated. RESULTS: There were no differences in baseline characteristics between the two groups. The overall 5-day failure rate and the cumulative 6-week mortality were 16.3% and 15.8%, respectively. The five-day failure rate and the cumulative 6-week mortality were not significantly different between the somatostatin and terlipressin groups. Hepatocellular carcinoma, the baseline serum creatinine level and endoscopic treatment for hemostasis were the significant predictors of 5-day failure; the baseline serum creatinine level was the predictor of 6-week mortality. CONCLUSIONS: Both somatostatin and terlipressin were effective and showed comparable efficacy for the control of the acute variceal bleeding in the setting of a combined therapeutic approach. The baseline serum creatinine level may be a significant predictor for patient failure at 5 days and the 6-week mortality.
Acute Disease ; Aged ; Carcinoma, Hepatocellular/complications ; Esophageal and Gastric Varices/complications/*drug therapy ; Female ; Gastrointestinal Hemorrhage/complications/*drug therapy ; Hemorrhage/complications/drug therapy ; Hemostasis, Endoscopic ; Humans ; Liver/*blood supply ; Liver Cirrhosis/*complications ; Liver Diseases/drug therapy ; Liver Neoplasms/complications ; Lysine Vasopressin/administration & dosage/*analogs & derivatives/therapeutic use ; Male ; Middle Aged ; Multivariate Analysis ; Somatostatin/administration & dosage/*therapeutic use ; Varicose Veins/complications/drug therapy ; Vasoconstrictor Agents/administration & dosage/*therapeutic use

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
Acetylation/drug effects ; Adolescent ; Adult ; Aged ; Apoptosis/*drug effects ; Cadherins/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; DNA Methylation/drug effects ; Enzyme Inhibitors/therapeutic use/*toxicity ; Frizzled Receptors/metabolism ; Gene Expression Regulation/drug effects ; HL-60 Cells ; Histone Deacetylase Inhibitors/therapeutic use/*toxicity ; Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism ; Histones/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use/*toxicity ; K562 Cells ; Leukemia/drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Middle Aged ; Piperazines/therapeutic use/toxicity ; Promoter Regions, Genetic ; Young Adult