10 research outputs found
Anticancer Efficacy of a Difluorodiarylidenyl Piperidone (HO-3867) in Human Ovarian Cancer Cells and Tumor Xenografts
The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl
piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer.
Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3,
PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably
and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward
ovarian cancer cells while sparing healthy cells. HO-3867 induced G2-M cell cycle arrest in A2780 cells
by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and
promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of
functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705)
and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including
Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure
disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of
the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot
analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1
and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited
significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway.
The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer
therapy
HO-3867, a Synthetic Compound, Inhibits the Migration and Invasion of Ovarian Carcinoma Cells through Downregulation of Fatty Acid Synthase and Focal Adhesion Kinase
Fatty acid synthase (FAS) and focal adhesion kinase (FAK), which are overexpressed in a variety of human
epithelial tumors, play a key role in the migration and invasion of cancer cells. Hence, strategies targeted at
inhibiting the FAS/FAK proteins may have therapeutic potential for cancer treatment. The goal of the present
study was to determine the effect of HO-3867, a synthetic compound, on the migratory ability of ovarian
cancer cells and to understand the mechanistic pathways including the involvement of FAS, FAK, and associated
signaling proteins. The study was done using two established human ovarian cancer cell lines, A2780
and SKOV3. Incubation with 10 μmol/L HO-3867 for 24 hours significantly inhibited the native as well as
the vascular endothelial growth factor (VEGF)–mediated migration and invasion of the cells. HO-3867
significantly attenuated FAS and FAK protein levels apparently through accelerated ubiquitin-dependent
degradation, as shown by a clear downregulation of isopeptidase USP2a. Exposure of cells to HO-3867
also significantly inhibited FAS activity and mRNA levels and a number of downstream proteins, including
phospho-extracellular signal–regulated kinase 1/2, phospho-human epidermal growth factor receptor 1, sterol
regulatory element binding protein 1, VEGF, and matrix metalloproteinase 2. Western blot and immunohistochemical
analyses of A2780 xenograft tumors in mice treated with HO-3867 showed significant reduction in FAS, FAK, VEGF, and downstream protein levels when compared with the untreated control. Collectively, the results showed that HO-3867 suppressed the migration and invasion of ovarian cancer cells by inhibiting the expression or activity of FAS and FAK proteins. The study suggests that molecular targeting
of FAS and FAK by HO-3867 may be a potential strategy for ovarian cancer therapy
Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung
Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung
Abstract—Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves
progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms
involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement
of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and
remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending
coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm
LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify
key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867.
LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg:
35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary
artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of
PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human
pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism
of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress
and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation
seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF. (Hypertension.
2013;61:593-601.
Cardiopulmonary Injury in the Syrian Hamster Model of COVID-19
The Syrian hamster has proved useful in the evaluation of therapeutics and vaccines for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). To advance the model for preclinical studies, we conducted serial sacrifice of lungs, large pulmonary vessels, and hearts from male and female Syrian hamsters for days 1–4, and 8 post-infection (dpi) following infection with a high dose of SARS-CoV-2. Evaluation of microscopic lung histopathology scores suggests 4 and 8 dpi as prime indicators in the evaluation of moderate pathology with bronchial hyperplasia, alveolar involvement and bronchiolization being key assessments of lung disease and recovery, respectively. In addition, neutrophil levels, red blood cell count and hematocrit showed significant increases during early infection. We present histological evidence of severe damage to the pulmonary vasculature with extensive leukocyte transmigration and the loss of endothelial cells and tunica media. Our evidence of endothelial and inflammatory cell death in the pulmonary vessels suggests endothelialitis secondary to SARS-CoV-2 epithelial cell infection as a possible determinant of the pathological findings along with the host inflammatory response. Lastly, pathological examination of the heart revealed evidence for intracardiac platelet/fibrin aggregates in male and female hamsters on 8 dpi, which might be indicative of a hypercoagulative state in these animals