Browsing by Author "Liu, Xinli"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item 2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor(2012-05) Koganti, Sivaramakrishna; Thekkumkara, Thomas; Abbruscato, Thomas J.; Karamyan, Vardan; Liu, XinliDelayed onset of cardiovascular(CVD) disease among females is not well understood, but could be in part due to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type I receptor (AT1R) as a key factor in the progression of CVD.In this study, we have examined the effects and mechanism of the estrogen metabolite, 2-Methoxyestradiol (2ME2), on AT1R expression.The study used rat liver epithelial cells as the primary cell model to determine the 2ME2 induced cellular signaling, the overall concept was further confirmed in rat aortic smooth muscle cells and further validated in vivo in an animal model of hypertension. When rat liver epithelial cells were exposed to 2ME2 for 24 hours, cells exhibited significant down-regulation of AngII binding and AT1R mRNA, independent of estrogen receptors (ERα/ERβ) with no change in receptor affnity.Significant inhibition of AngII mediated increase in intracellular Ca+2 and increased phopsphorylation of ERK1/2 were also observed.Similar analyses in stably transfected CHO cell lines with a constitutively active cytomegalovirus (CMV) promoter showed no change in AT1R expression suggesting the transcriptional regulation.2ME2 has been shown to bind specifically to endoplasmic reticulum bound G-protein coupled receptor 30(GPR30), activating matrix metalloprpteinases (MMPs) to induce epidermal growth factor receptor (EGFR) activation ultimately leading to AT1R down-regulation.2ME2 treatment showed significant down-regulation of systolic, diastolic and mean arterial blood pressure, as well as a decrease in body weight in spontaneously hypertensive rats (SHR).Consistent with the reduction in blood pressure, we observed AT1R protein and mRNA expression down-regulation in the renal cortical tissue. In summary, as AT1R plays a critical role in the control of cardiovascular diseases, 2ME2 induced changes in receptor expression may provide beneficial effects to the cardiovascular, as well as other systems.Item Tumor Vascular Permeability and Drug Delivery in a Preclinical Model of Brain Metastases of Breast Cancer(2010-12) Mittapelli, Rajendar; Lockman, Paul R.; Abbruscato, Thomas J.; Liu, Xinli; Smith, Quentin R.; Srivastava, SanjayIntroduction: Metastatic brain tumors are a common complication of most solid tumors. Brain metastases occur in 30-40% of metastatic breast cancer patients. One year survival after diagnosis of a brain metastasis is approximately 20%. The incidence of brain metastasis may be rising, particularly in the subset of patients with Her-2 amplified tumors. Little quantitative information exists on the BTB permeability in brain metastases. Further, most prior studies have used intracranial implantation models which do not capture many of the key steps in metastatic tumor implantation and development in CNS. In this dissertation we describe sensitive new fluorescent and phosphorescent imaging techniques to measure BTB permeability in brain metastases of breast cancer in mice. Further, this dissertation also shows the potential of a novel bioconjugate system for targeting metastatic lesions. Methods: Female mice were injected with either MDA-MB-231-Br-Her2 or 4T1Br5 (brain seeking metastatic lines) via left cardiac ventricle. Tumors developed over ~2-6 weeks, after which animals were injected with 14C-AIB and TX Red 3kDa. Tracer concentration in blood and brain were determined using fluorescent microscopy and autoradiography. Further, to target the metastatic lesions, a small molecular weight hyaluronic acid paclitaxel conjugate was explored as a mechanism to deliver drugs into metastasis cells. Results: A striking finding is the marked heterogeneity of BTB integrity among metastases. Based upon analysis of n>2000 metastases, statistically significant changes in BTB permeability were observed in ~90% of 231-BR-Her2 and ~96% of 4T1-BR5 brain metastases. No correlation was found between changes in the integrity of the BTB and metastasis size or tumor morphology. Further, the HA-paclitaxel bypassed tumor P-gp, accumulated at higher amounts than free paclitaxel, and showed similar cytotoxicity as that of paclitaxel. Conclusions: Tumor vascular permeability is heterogenous and is consistent with the limited and variable clinical efficacy of most chemotherapeutic drugs for brain metastases. Further, we propose that HA-paclitaxel may improve drug delivery to metastatic lesions.