scholarly journals The effect of 10 weeks endurance training on protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 in cardiac myocytes of female

2021 ◽  
Vol 43 (1) ◽  
pp. 134-141
Author(s):  
Naiemeh Yazdan Shenas ◽  
Maghsoud Peeri ◽  
Maryam Delfan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endurance Training ◽  
Cardiac Myocyte ◽  
Training Session ◽  
Training Group ◽  
Left Ventricular ◽  
Control Group ◽  
Protein Levels ◽  
Cardiac Atrophy

Background: Cardiac atrophy is the most important complications resulted by cancer Given the role of exercise in protecting against cancer complications, the aim of the present study was to determine the effect of 10 weeks of endurance training on protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 in cardiac myocyte of female Balb/C mic with breast cancer. Methods: The present study was an experimental study. Twelve female BALB/c mice after inducing breast cancer were randomly divided into two groups (n=6) including endurance training group (E) and the control group (C). E group performed 65 min at a constant running speed corresponding to 60% vVo2max at 15% inclination, ten weeks (five days a week). The Left ventricular of animals was extracted 24h following the last training session. Protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 were determined by, respectively, western blot and qReal-time PCR. Statistic data values also were measured by independent samples t-test at the 0.05 levels of significance. Results: The results of the present study showed a significant decreased in cardiac protein levels of NF-kB (p<0.001) and cardiac gene expression of Atrogin-1 (p<0.001) and MuRF-1 (p=0.003) in comparison with control group. Endurance training group had significantly greater heart weights compared to control group (p<0.001). Conclusion: it seems that 10 weeks of endurance training possibly affect mechanisms involved in cancer-induced cardiac atrophy such as NF-kB/Atrogin-1/MuRF-1 axis results in decreasing cardiac atrophy in mice with breast cancer.

scholarly journals Effect of Endurance Training and Stem Cell on Fgf2 and Mmp13 Gene Expression in Knee Tissue of Rats with Osteoarthritis

2021 ◽  
Author(s):  
Mahnaz Alinejad ◽  
Alireza Barari ◽  
Asieh Abbasi Daloii ◽  
Parvin Farzanegi
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Endurance Training ◽  
Training Group ◽  
Saline Group ◽  
Cartilage Tissue ◽  
Control Group ◽  
Significant Difference ◽  
The Difference ◽  
Post Hoc

Introduction: The aim of this study was to investigate the effect of endurance training and stem cell injection on FGF2 and MMP13 gene expression in knee tissue of rats with knee osteoarthritis. Methods: The type of study was an experimental one.Male Wistar rats were randomly divided into 5 groups: control - healthy, control - patient, patient - stem cell, patient - training, and patient - training - stem cell. The training program consisted of 30 minutes of running on a treadmill with no slope at 16 m / min for the first week, with 1 m / min added weekly. Rats received MSCs through intracellular injection of 1*106 cells / kg. Expression of FGF2 and MMP13 genes was measured by Real Time PCR. One way ANOVA and if there was a significant difference, Tukey post hoc test were used to determine the difference between groups. All statistical analyzes were performed using SPSS version 20. Results: Data analysis showed that training and stem cell therapy have significantly increased in genes expression of FGF2 and MMP-13 in mice with osteoarthritis (p <0.000). Moreover, Tukey post hoc test showed a significant difference in the level of FGF2 changes in the training-stem cell groups compared to the training group and the saline group (p=0.000‌). There was also a significant difference between the MMP-13 follow-up test with the control group with the saline group, the training group and the stem cell with the train-stem cell, and the saline group with the training group9(P=0.000‌). Conclusion: The results showed that FGF2 levels and MMP13 in the cartilage tissue of mice with osteoarthritis have increased and endurance training and stem cells therapy caused a decrease in the level of factors.  

Repression of protocadherin 17 is correlated with elevated angiogenesis and hypoxia markers in female patients with breast cancer

2021 ◽  
pp. 1-10
Author(s):  
Sanaa A. El-Benhawy ◽  
Samia A. Ebeid ◽  
Nadia A. Abd El Moneim ◽  
Rabie R. Abdel Wahed ◽  
Amal R.R. Arab
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Stage ◽  
Suppressor Gene ◽  
Normal Breast ◽  
Vital Role ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Cd34 Cells ◽  
Breast Tissues

BACKGROUND: Altered cadherin expression plays a vital role in tumorigenesis, angiogenesis and tumor progression. However, the function of protocadherin 17 (PCDH17) in breast cancer remains unclear. OBJECTIVE: Our target is to explore PCDH17 gene expression in breast carcinoma tissues and its relation to serum angiopoietin-2 (Ang-2), carbonic anhydrase IX (CAIX) and % of circulating CD34+ cells in breast cancer patients (BCPs). METHODS: This study included Fifty female BCPs and 50 healthy females as control group. Cancerous and neighboring normal breast tissues were collected from BCPs as well as blood samples at diagnosis PCDH17 gene expression was evaluated by RT-PCR. Serum Ang-2, CAIX levels were measured by ELISA and % CD34+ cells were assessed by flow cytometry. RESULTS: PCDH17 was downregulated in cancerous breast tissues and its repression was significantly correlated with advanced stage and larger tumor size. Low PCDH17 was significantly correlated with serum Ang-2, % CD34+ cells and serum CAIX levels. Serum CAIX, Ang-2 and % CD34+ cells levels were highly elevated in BCPs and significantly correlated with clinical stage. CONCLUSIONS: PCDH17 downregulation correlated significantly with increased angiogenic and hypoxia biomarkers. These results explore the role of PCDH17 as a tumor suppressor gene inhibiting tumor growth and proliferation.

Abstract 3791: Improved Ventricular-Arterial Coupling After 4 Weeks of Exercise Training in Patients with Chronic Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Marcus Sandri ◽  
Stephan Gielen ◽  
Norman Mangner ◽  
Volker Adams ◽  
Sandra Erbs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Exercise Training ◽  
Endothelial Function ◽  
Training Group ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Lv Function ◽  
Ventricular Ejection Fraction

Background: The concept of ventricular-arterial coupling implies that LV-function is determined by the three factors left ventricular diastolic, left ventricular systolic and arterial elastance. We have previously documented an improvement in endothelial function and systolic LV-function in patients with chronic heart failure (CHF) after 6 months of exercise training (ET). It remains, however, unclear, how shorter ET periods may affect endothelial, systolic and diastolic ventricular function as echocardiographic parameters related to ventricular arterial coupling in patients with CHF. METHODS: In this ongoing study we randomised 43 patients with stable CHF (age 60.3 ± 2.9 years, EF 27.4 ± 1.7%, VO 2 max 14.7 ± 4.3ml/kg*min) to a training or a control group (C). Patients in the training group exercised 4 times daily at 70% of the individual heart rate reserve for 4 weeks under supervision. At baseline and after 4 weeks the E/A ratio and septal/lateral E’/A’ velocities were determined by echocardiography with tissue Doppler. Exercise capacity was measured by ergospirometry and flow-mediated dilatation (FMD) was assessed by high-resolution radial ultrasound. RESULTS: After only 4 weeks of ET oxygen uptake at peak exercise increased from 14.9 ± 3.3 to 18.1 ± 4.7 ml/min/kg, (p<0.01 vs. C) in training subjects. Left ventricular ejection fraction improved from 26.8 ± 4.6 to 33.1 ± 5.5% (p<0.05 vs. C) in patients of the training group while it remained unchanged in the control group. E/A-ratio mended from 0.63 ± 0.12 to 0.81 ± 0.22 (p<0.01 vs. C) in training patients. Septal E’ velocities increased from 5.5 ± 0.5 to 7.8 ± 1.4 cm/s in training patients (p<0.05 vs. C). FMD of the radial artery improved from 8.2 ± 2.1 to 15.2 ± 3.8% (p<0.01 vs. C) as a result of ET. CONCLUSIONS: Only 4 weeks of endurance training are highly effective with significantly improved FMD accompanied by an emended systolic and diastolic LV-function. We hypothesise that the improvement in LV-EF in training patients may be caused by a corrected ventricular-arterial coupling: ventricular diastolic relaxation and effective endothelial function are ameliorated resulting in an augmentation of stroke volume.

scholarly journals The relationship between the expression of PLIN3 and PLIN5 protein flowing endurance training in streptozotocin rats

2019 ◽  
Vol 21 (4) ◽  
pp. 194-199
Author(s):  
Mahdi Ghafari ◽  
Ebrahim Banitalebi ◽  
Mohamad Faramarzi
Keyword(s):  
Insulin Resistance ◽  
Endurance Training ◽  
High Intensity ◽  
Training Group ◽  
Control Group ◽  
High Intensity Training ◽  
Significant Difference ◽  
Post Hoc ◽  
The Relationship ◽  
Intensity Training

Background and aims: Intermuscular lipolysis disorder plays an important role in insulin resistance and diabetes mellitus and perilipin PLIN5 and PLIN3 are the key proteins in regulating muscle cellular lipolysis. Therefore, the purpose of this study was to examine the relationship between the expression of PLIN3 and PLIN5 protein following endurance training in streptozotocin (STZ) rats. Methods: A number of 24 male Wistar rats were randomly divided into low endurance training group (n = 8), high-intensity training group (n = 8), and control group (n = 8). Diabetes was induced in every rat by STZ injection. Three days after injection, the blood samples were taken from the cut tip of the tails of the mice and animals with blood glucose greater than 300 mg/dL were considered diabetic. The training program included eight weeks of aerobic training at different intensities. Training in high- and low-intensity groups included 22-25 and 5-8 m/min of training. Finally, one-way analysis of variance (ANOVA) and correlation was used to determine the significance of the differences between variables, followed by utilizing Tukey’s post-hoc test for significance. Results: The comparison between the groups by ANOVA showed significant differences in PLIN3 (P=0.0006) and PLIN5 (P=0.012). The results of Tukey post hoc test also demonstrated a statistical difference between the mean values of diabetic control group and high-intensity endurance group regarding PLIN3 (P=0.01) and PLIN5 (P=0.009), but no significant increase was observed in the lowintensity exercise group as compared to the control group (PLIN3, P=0.067 & PLIN5, P=0.44). As regards insulin resistance, there was a significant difference among the three groups (P=0.0001). Eventually, the result of the correlation between PLIN3 and PLIN5 showed similar enhancement by increasing the intensity (P=0.0026). Conclusion: According to research results, high-intensity endurance training increased the expression of PLIN3 and PLIN5 in diabetic specimens and PLIN3 and PLIN5 followed a similar increase pattern in high-intensity training

scholarly journals Mummy Induces Apoptosis Through Inhibiting of Epithelial-Mesenchymal Transition (EMT) in Human Breast Cancer Cells

2020 ◽  
Vol 9 ◽  
pp. 1812
Author(s):  
Solmaz Rahmani Barouji ◽  
Arman Shahabi ◽  
Mohammadali Torbati ◽  
Seyyed Mohammad Bagher Fazljou ◽  
Ahmad Yari Khosroushahi
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Control Group ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Mcf 7

Background: Mummy (Iranian pure shilajit) is a remedy with possessing anti-inflammatory, antioxidant and anticancer activities. This study aimed to examine mummy effects on epithelial-mesenchymal transition (EMT) and invasiveness of MCF-7 and MDA-MB-231 breast cancer (BC) cell lines with underlying its mechanism. Materials and Methods: The dose-dependent inhibitory effect of the mummy on cell proliferation in vitro was determined using the MTT assay.  Flow cytometry and 4’,6-diamidino-2-phenylindole dihydrochloride staining were respectively used for quantitative and qualitative analysis of cellular apoptosis, and gene expression analysis was conducted using real-time PCR. Results: MDA-MB-231 showed more sensitivity than the MCF-7 cell line to the anticancer activity of mummy, while mummy did not exhibit significant cell cytotoxicity against human normal cells (MCF-10A). The gene expression profile demonstrated a significant decrease in TGF-β1, TGF-βR1, TWIST1, NOTCH1, CTNNB1, SRC along with an increase in E-cadherin mRNA levels in mummy treated cells compared to the untreated control group (P≤0.05). Conclusion: Mummy triggers inhibition of EMT and metastasis in breast cancer cells mainly through the downregulation of TGFβ1 activity, and more studies required to find its specific anticancer activity with details. [GMJ.2020;9:e1812]

scholarly journals The effect of 8 weeks endurance exercise on the content of total and phosphorylated AKT1, mTOR, P70S6K1 and 4E-BP1 in skeletal muscle FHL of rats with type 2 diabetes

2019 ◽  
Author(s):  
Saeedeh Shadmehri ◽  
Mohammad Sherafati Moghadam ◽  
Farhad Daryanoosh ◽  
Shiva Jahani Golbar ◽  
Nader Tanideh
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Training Program ◽  
Endurance Training ◽  
Endurance Exercise ◽  
Training Group ◽  
Control Group ◽  
Total P

Introduction: The mTOR pathway in skeletal muscle plays a very important role in the protein synthesis process, which plays a very important role in proteins. The role of endurance exercise has not yet been studied in this important pathway in protein synthesis in people with type 2 diabetes. The purpose of the present study was to investigate the effect of 8 weeks endurance training on the content of total and phosphorylated AKT1, mTOR, P70S6K1 and 4E-BP1 in skeletal muscle FHL of rats with type 2 diabetes. Methods: In this experimental study, 16 Sprague-Dawely male rats with average weight of 270±20 were selected and randomly divided into two groups: control (n=8) and endurance training (n=8). The training group exercised according to the training program 4 days a week for 8 weeks. While the control group had no training program. T-test and SPSS V-19 were used to analyze the data. Results: There was not observed any significant difference in the content of total (P=0.58) and phosphorylated (P=0.33) AKT1, total (P=0.47) and phosphorylated (P=0.78) mTOR, total (P=0.24) and phosphorylated (P=0.12) P70S6K1 and total (P=0.45) and phosphorylated (P=0.48) 4E-BP1 proteins in the endurance training group compared to the control group. Conclusion: Endurance training for 8 weeks could not increase the total and phosphorylated content proteins of the present study; therefore, it cannot lead to protein synthesis or muscle hypertrophy through mTORC1 pathway.

Benefits of aerobic training in girls with precocious puberty: involvement of CRP and cortisol

2019 ◽  
Vol 32 (9) ◽  
pp. 1005-1011 ◽  
Author(s):  
Ali Heidarianpour ◽  
Elnaz Shokri ◽  
Tayebe Baghian ◽  
Behnaz Shokri
Keyword(s):  
Precocious Puberty ◽  
Repeated Measures ◽  
Aerobic Training ◽  
Training Session ◽  
Training Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Significant Difference ◽  
Cortisol Levels ◽  
Serum Crp

Abstract Background The aim of this study was to investigate the effect of 12 weeks of aerobic training, 4 weeks of detraining and use gonadotropin-releasing hormone agonist (GnRHa) on serum C-reactive protein (CRP) and cortisol levels in girls with central precocious puberty (CPP). Methods Forty-five girls (aged 6–8 years) with precocious puberty were randomly divided into three groups (medication, training and medicine + training groups). Fifteen healthy girls (without precocious puberty) were also included as the control group. Serum CRP and cortisol levels were measured at baseline by the enzyme-linked immunosorbent assay (ELISA) technique. Then, the experimental groups performed an aerobic training program for 3 days/week 20–75 min per day at 45–75% maximum heart rate for 12 weeks. The medication groups also received GnRHa during the study, once a month (1 mL every 4 weeks) by intramuscular injection. Serum CRP and cortisol levels were measured again 48 h after the last training session and also after 4 weeks of detraining. Results Analysis of variance (ANOVA) with repeated measures showed a significant decrease in CRP (p = 0.02) and cortisol levels (p = 0.01) in the training group and the medicine + training group. Detraining led to return of CRP and cortisol levels to the pre-training levels (p = 0.001). No significant difference in serum CRP (p = 0.43) and cortisol levels (p = 0.06) was observed in the medication group. Further, no significant difference was observed between groups in CRP and cortisol. Conclusions Long-term regular moderate training decreases inflammation indices, and detraining eliminates the benefits of training in girls with precocious puberty.

scholarly journals Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients

2019 ◽  
Vol 22 (1) ◽  
Author(s):  
Qiong Gao ◽  
◽  
Elena López-Knowles ◽  
Maggie Chon U. Cheang ◽  
James Morden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Proliferation ◽  
Aromatase Inhibitor ◽  
Breast Cancer Mortality ◽  
Global Gene Expression ◽  
Therapy Resistance ◽  
Control Group ◽  
Short Term Exposure ◽  
The Impact

Abstract Background Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance. Methods Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67. Results High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2− tumours. In HER2− tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) including PERP and YWHAQ, the two most significant, and the transcription co-regulators (SAP130, HDAC4, and NCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, and IGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2− and HER2+ patients. Conclusions There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors. Trial registration ISRCTN, ISRCTN63882543, registered on 18 December 2007.

Baroreflex function and cardiac structure with moderate endurance training in normotensive men

1993 ◽  
Vol 74 (5) ◽  
pp. 2469-2477 ◽  
Author(s):  
M. P. McDonald ◽  
A. J. Sanfilippo ◽  
G. K. Savard
Keyword(s):  
Heart Rate ◽  
Exercise Training ◽  
Arterial Pressure ◽  
Endurance Training ◽  
Sinus Node ◽  
Left Ventricular ◽  
Control Group ◽  
Cardiac Structure ◽  
Baroreflex Function ◽  
Cardiopulmonary Baroreflex

Changes in arterial and cardiopulmonary baroreflex function and cardiac structure were followed throughout 10 wk of moderate endurance training [60 min of cycling, 3 days/wk, 60% maximal O2 uptake (VO2max)] in sedentary normotensive men (22–34 yr old). Subjects were randomly assigned to an exercise training group (ET; n = 9) or to a control group (UT; n = 4). Decreases in resting heart rate (8.9 +/- 2.6%, P < 0.01) and mean arterial pressure (7.0 +/- 2.3%, P < 0.05) and an increase in VO2max occurred after 10 wk in ET. An increase in the gain or slope of the spontaneous baroreflex response at rest was found after 10 wk in ET (50.1 +/- 6.3%, P < 0.01) but not in UT. An upward shift in the resting carotid-cardiac baroreflex response curve also occurred after 10 wk in ET, although the maximum range and gain of the response and the vagally mediated peak reflex sinus node responses were unchanged. Cardiopulmonary baroreflex function (reflex changes in forearm vascular conductance) and measured indexes of left ventricular structure were not altered in either ET or UT, although peak transmitral inflow velocity increased in ET (P < 0.05). These findings demonstrate that moderate exercise training results in an enhancement in the ability to reflexly adjust heart rate with spontaneous changes in arterial pressure within the operating range. This occurs independently of any changes in carotid-cardiac baroreflex function over the full response range in cardiopulmonary baroreflex function or in cardiac structure.

Cytotoxicity Assessment of Quassinoids Neosergeolide and Isobrucein B toward Hematopoietic and Solid Malignancies Identifies STAT3 Activation To Be Predictive of Antitumor Response.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1394-1394
Author(s):  
Mitsuteru Hiwatari ◽  
Jingqiu Dai ◽  
Wei Liu ◽  
Yu-Dong Zhou ◽  
Dale G. Nagle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cytotoxic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Strong Support ◽  
Luciferase Reporter ◽  
Control Group ◽  
Antitumor Effects ◽  
Protein Levels ◽  
Ic50 Values

Abstract Quassinoids are natural product compounds known to possess tumor cytotoxicity and antimalarial activity. Neosergiolide and isobrucein B are two quassinoids previously isolated from roots and stems of Picrolemma sprucei. In screening studies to identify inhibitors that target STAT3, we discovered neosergeolide and isobrucein B as active compounds. Approximately 5000 plant-derived extracts were screened using a cell line that stably expresses a STAT3-dependent luciferase reporter and NPM-ALK, which constitutively induces STAT3 transcriptional activity. Of 25 total hits, a P. sprucei extract was potent and selective for STAT3 inhibition, and bioassay-guided isolation identified neosergeolide and isobrucein B as the inhibitory compounds. Western blot analysis confirmed that neosergeolide and isobrucein B not only inhibit the tyrosine phosphorylation and activation of STAT3 but also decrease total STAT3 protein levels via a mechanism due in part to enhanced proteasome-mediated degradation. Small-molecule proteasome inhibitors such as MG132 and ALLN reversed the ability of the two quassinoids to decrease STAT3 protein levels; furthermore, simultaneous incubation of various hematopoietic malignancy cell lines with either neosergeolide or isobrucein B and MG132 or ALLN antagonized the cytotoxic activity of the quassinoids. Assessment of neosergiolide and isobrucein B antitumor effects using an XTT assay revealed both compounds to possess potent cytotoxic activity across a broad spectrum of hematopoietic malignancies, with T-leukemias/lymphomas being especially responsive. For example, mycosis fungoides (MF)- and Sezary syndrome (SS)-derived cell lines, as well as non-MF/SS cutaneous T-cell lymphoma (CTCL) lines, were potently inhibited by both quassinoids (neosergiolide IC50 values: MAC-1, 11.6 nM; MAC-2A, 6.9 nM; Hut-78, 6.6 nM; HH, 4.3 nM; MJ, 7.0 nM; isobrucein B IC50 values: MAC-1, 31.9 nM; MAC-2A, 72.3 nM; Hut-78, 23.5 nM; HH; 20.3 nM; MJ, 13.5 nM). Non-hematopoietic cell lines representing various solid tumors also exhibited potent cytotoxic responses to the quassinoids (e.g., gastric carcinoma line AGS [neosergiolide IC50: 16.9 nM; isobrucein B IC50: 114.9 nM]). With rare exceptions, the cytotoxicity of the quassinoids against a specific tumor cell line correlated with STAT3 activation status; for example, breast cancer line MCF7 with inactive STAT3 was resistant to both quassinoids even at the maximum concentration tested (6.25 μM), whereas breast cancer lines MDA-MB-468 and MDA-MB-435s with activated STAT3 were inhibited by both compounds at low concentrations (neosergiolide IC50: MDA-MB-435s, 31.3 nM; MDA-MB-468, 29.9 nM; isobrucein B IC50: MDA-MB-435s, 209.3 nM; MDA-MB-468, 356.8 nM). The in vitro antitumor activity of the two quassinoids could also be demonstrated in vivo. For example, isobrucein B (1.0 mg/kg IP once q 3d x 5 doses) could be safely administered and potently inhibited the growth in SCID mice of the CD30+ primary CTCL MAC-1 cell line; mice at treatment day 16 showed average subcutaneous tumor volumes of 3839 ± 863 (s.e.) mm3 in the vehicle-control group and 913 ± 349 (s.e.) mm3 in the isobrucein B group (P=0.008, t-test). These results provide strong support for STAT3 targeting in antitumor drug discovery and suggest that quassinoids may have utility in such an approach.

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