Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD.Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.

Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD.Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.

Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD.Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.

Licochalcone C (LCC; PubChem CID:9840805), a chalcone compound originating from the root of Glycyrrhiza inflata, has shown anticancer activity against skin cancer, esophageal squamous cell carcinoma, and oral squamous cell carcinoma. However, the therapeutic potential of LCC in treating colorectal cancer (CRC) and its underlying molecular mechanisms remain unclear. Chemotherapy for CRC is challenging because of the development of drug resistance. In this study, we examined the antiproliferative activity of LCC in human colorectal carcinoma HCT116 cells, oxaliplatin (Ox) sensitive and Ox-resistant HCT116 cells (HCT116-OxR). LCC significantly and selectively inhibited the growth of HCT116 and HCT116-OxR cells. An in vitro kinase assay showed that LCC inhibited the kinase activities of EGFR and AKT. Molecular docking simulations using AutoDock Vina indicated that LCC could be in ATP-binding pockets. Decreased phosphorylation of EGFR and AKT was observed in the LCC-treated cells. In addition, LCC induced cell cycle arrest by modulating the expression of cell cycle regulators p21, p27, cyclin B1, and cdc2. LCC treatment induced ROS generation in CRC cells, and the ROS induction was accompanied by the phosphorylation of JNK and p38 kinases. Moreover, LCC dysregulated mitochondrial membrane potential (MMP), and the disruption of MMP resulted in the release of cytochrome c into the cytoplasm and activation of caspases to execute apoptosis. Overall, LCC showed anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, inducing ROS generation and disrupting MMP. Thus, LCC may be potential therapeutic agents for the treatment of Ox-resistant CRC cells.

The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anticancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

BACKGROUND: Inflammation plays a key role in the pathogenesis of an in-stent restenosis because it promotes neointimal proliferation. This study was performed to determine responses of the C-reactive protein (CRP) in unstable angina patients with an in-stent restenosis undergoing repeated percutaneous transluminal coronary angioplasty (re-PTCA). METHODS: The study subjects (unstable angina) were classified into 2 groups:Group A (n=30, 15 men, mean age 62 years) had a re-PTCA for an in-stent restenosis lesion and Group B (n=60, 33 men, mean age 63 years) underwent a stent implantation for a de novo lesion. RESULTS: The baseline CRP levels in group A were significantly lower than in group B, as well as 6 and 24 hours after intervention. Twenty four hours after intervention, the CRP levels increased (>4 mg/L) in 3 out of 30 patients (10%) of group A but increased in 32 out of 60 patients (53%) in group B (p<0.001). The differences in the CRP levels between the baseline and 24 hours after intervention were significantly lower in group A than in group B (0.8 and 2.15 mg/L, respectively, p<0.001). In group B, the serum CRP levels 24 hours after intervention were significantly higher than the baseline levels (p<0.05), but not in group A. CONCLUSION: The CRP expression level is significantly lower in unstable angina patients undergoing a re-PTCA for an in-stent restenosis than those undergoing a stent implantation for a de novo lesion.
Angina, Unstable* ; Angioplasty* ; Angioplasty, Balloon, Coronary ; C-Reactive Protein ; Coronary Restenosis ; Humans ; Inflammation ; Male ; Stents

BACKGROUND AND OBJECTIVES: Electrical dyssynchronicity (Dsyn) appears to be prognostic of survival in congestive heart failure (CHF). Recent study has shown some discrepancy between the electrical Dsyn and the Doppler tissue image (DTI) assessed mechanical Dsyn. The aim of our study was to evaluate the relationship between the QRS duration and DTI assessed Dsyn. SUBJCETS AND METHODS: One hundred and forty patients, with CHF and left ventricular ejection fractions < or =40%, were enrolled. DTI was performed on 5-basal and 5-mid segments to assess the time from the R-wave to the peak systolic velocity (RS time). A QRS duration >130 msec, standard deviation (SD) of the RS time >40 msec, or a difference in the maximal and minimal RS times (RS time-diff) >100 msec were indicators of'Dsyn'. RESULTS: The prevalence of myocardial Dsyn, by QRS duration, SD of the RS time and the RS time-diff were 19, 43 and 47%, respectively. The SD of the RS time (49.8+/-23.6 vs. 36.6+/-20.7, p<0.01) and the RS time-diff (139.2+/-63.2 vs. 98.0+/-54.3, p<0.01) were prolonged in the wide (>130 msec) compared with the narrow QRS group. There was also a weak positive correlation between the QRS duration and the SD of the RS time (R=0.34, p<0.001) and the RS time-diff (R=0.38, p<0.001). However, from a cross-tabulation analysis, more than one third of patients had a discrepancy between QRS duration and DTI assessed mechanical Dsyn. From a multivariate analysis, a major determinant of the SD of the RS time was the QRS duration. CONCLUSION: Although a major determinant of the DTI assessed Dsyn was the QRS duration, more than one-third of patients had a discrepancy between electrical and mechanical Dsyn. Therefore, not only the QRS duration, but the DTI assessed Dsyn, should be measured when considering cardiac resynchronization therapy.
Cardiac Resynchronization Therapy ; Diagnosis* ; Electrocardiography* ; Estrogens, Conjugated (USP)* ; Heart Failure* ; Humans ; Multivariate Analysis ; Prevalence ; Stroke Volume

BACKGROUND AND OBJECTIVES: Electrical dyssynchronicity (Dsyn) appears to be prognostic of survival in congestive heart failure (CHF). Recent study has shown some discrepancy between the electrical Dsyn and the Doppler tissue image (DTI) assessed mechanical Dsyn. The aim of our study was to evaluate the relationship between the QRS duration and DTI assessed Dsyn. SUBJCETS AND METHODS: One hundred and forty patients, with CHF and left ventricular ejection fractions < or =40%, were enrolled. DTI was performed on 5-basal and 5-mid segments to assess the time from the R-wave to the peak systolic velocity (RS time). A QRS duration >130 msec, standard deviation (SD) of the RS time >40 msec, or a difference in the maximal and minimal RS times (RS time-diff) >100 msec were indicators of'Dsyn'. RESULTS: The prevalence of myocardial Dsyn, by QRS duration, SD of the RS time and the RS time-diff were 19, 43 and 47%, respectively. The SD of the RS time (49.8+/-23.6 vs. 36.6+/-20.7, p<0.01) and the RS time-diff (139.2+/-63.2 vs. 98.0+/-54.3, p<0.01) were prolonged in the wide (>130 msec) compared with the narrow QRS group. There was also a weak positive correlation between the QRS duration and the SD of the RS time (R=0.34, p<0.001) and the RS time-diff (R=0.38, p<0.001). However, from a cross-tabulation analysis, more than one third of patients had a discrepancy between QRS duration and DTI assessed mechanical Dsyn. From a multivariate analysis, a major determinant of the SD of the RS time was the QRS duration. CONCLUSION: Although a major determinant of the DTI assessed Dsyn was the QRS duration, more than one-third of patients had a discrepancy between electrical and mechanical Dsyn. Therefore, not only the QRS duration, but the DTI assessed Dsyn, should be measured when considering cardiac resynchronization therapy.
Cardiac Resynchronization Therapy ; Diagnosis* ; Electrocardiography* ; Estrogens, Conjugated (USP)* ; Heart Failure* ; Humans ; Multivariate Analysis ; Prevalence ; Stroke Volume

BACKGROUND AND OBJECTIVES: The recovery of the left ventricular ejection fraction (LVEF) appeared to be prognostic of survival in congestive heart failure (CHF). The aim of our study was to evaluate the parameters that appear to predict the LVEF recovery in CHF. SUBJECTS AND METHODS: Forty-nine patients, with CHF and a LVEF< 35%, were enrolled. Doppler myocardial imaging was performed on 5-basal and 5-mid segments in order to assess the systolic duration, the time from the R-wave to the peak systolic velocity (RS time) and the time from the R-wave to the peak early diastolic velocity (RE time). The standard deviation (SD) of the RS time was an indicator of the 'systolic synchronicity'. After at least 3 months of full medical therapy, a follow-up echocardiography was performed. According to the changes in the LVEF, the patients were divided into groups I (< 5%, n=29) and II (> or =5%, n=20). RESULTS: The baseline clinical and echocardiographic parameters were similar in both groups. In group II, the LV end-systolic and end-diastolic volumes were decreased, but the LVEF was increased by up to 44% at the follow-up. The right ventricular annulus velocity (group I: 6.7+/-2.1 vs. group II: 8.0+/-2.0 cm/sec, p< 0.05), the use of beta-blocker (69 vs. 100%, p< 0.05) and the SD of the RS time (46+/-21 vs. 21+/-12, p< 0.01) were significantly different between the two groups. However, the systolic duration and the SD of the RE time were similar in the two groups. From a multivariate analysis, only the SD of the RS time was an independent predictor of the LVEF recovery. CONCLUSION: Myocardial systolic synchronicity is an important predictor of the LVEF recovery.
Echocardiography ; Estrogens, Conjugated (USP)* ; Follow-Up Studies ; Heart Failure* ; Heart Ventricles* ; Humans ; Multivariate Analysis ; Recovery of Function* ; Stroke Volume

BACKGROUND AND OBJECTIVES: Several echocardiographic methods, such as ejection fraction, fractional shortening, and Doppler tissue imaging (DTI), have been developed to quantify systolic function but all had several important limitations. The purpose of this study was to quantify the regional wall motion abnormality, using strain, in an acute myocardial infarction, compared with a visual estimation. SUBJECTS AND MEHTODS: Forty-five patients, with acute anterior (n=28) and inferior myocardial (n=17) infarctions, who underwent color DTI, were examined using longitudinal strain and standard echocardiography, and the results were compared with 54 normal controls. A total of 594 segments [3 segments (apical, mid and basal portion) of septum and inferior wallx99 patients] were evaluated. RESULTS: In the normal control group, the strain was uniformly distributed in all segments (-20%~-23%). In the infarction groups, the strain was negatively related with the wall motion score. The strain of the apical segments and mid-septum was decreased in the anterior wall infarctions, and the strain of basal septum and mid to basal inferior wall was decreased in the inferior wall infarctions. The dyskinetic segments showed positive strain. CONCLUSION: This study validates strain as a superior method for the quantification of the regional wall motion abnormality in an acute myocardial infarction than visual estimation.
Echocardiography ; Humans ; Infarction ; Myocardial Infarction*