Sustained exercise-induced elevations in shear rate (SR) have been well established as beneficial for improving endothelial function. However, the impact of intermittent fluctuations in SR is not understood. We investigated the effect of intermittent SR elevations compared with sustained elevations on peripheral endothelial function. Brachial artery flow-mediated dilation (FMD) was assessed in 13 adults (9 M/4 F; 22 ± 4 yr) before and after 30 min of handgrip exercise. Three different rhythmic forearm exercise interventions were performed at a rate of 20 contractions/min. Intermittent exercises (6 × 3 min exercise interspersed by 2 min of rest) were performed at 25% (INT-25%) and 15% (INT-15%) maximum voluntary contraction (MVC), and continuous exercise was completed at 15% MVC. Brachial artery diameter and velocity were measured using Doppler ultrasound. The total increase in SR above baseline throughout exercise was greater during INT-25% (4,441 ± 516 s^-1) and continuous (4,070 ± 407 s^-1) compared with INT-15% (2,811 ± 342 s^-1, P < 0.05). The %FMD increased following all exercises (INT-25%: 5.7 ± 1.2% to 8.1 ± 1.2%; INT-15%: 5.2 ± 1.2% to 7.0 ± 1.1%; continuous: 5.5 ± 1.3% to 6.8 ± 1.3%, P < 0.05 for all). The increase following INT-25% was significantly greater than INT-15% and continuous (P < 0.05 for both). Normalized FMD to shear rate area under the curve increased with intermittent exercise (INT-25%: 2.2 ± 0.2% to 3.4 ± 0.3%; INT-15%: 2.1 ± 0.2% to 3.2 ± 0.2%, P < 0.05 for both) but did not following continuous (2.1 ± 0.2% to 2.5 ± 0.1%, P = 0.06). The increase in normalized FMD with intermittent exercises were greater than continuous (P < 0.05 for both). These findings suggest intermittent fluctuations in SR during handgrip exercise may be more beneficial than sustained elevations on improving peripheral endothelial function.NEW & NOTEWORTHY Exercise-induced increases in shear rate is a well-established stimulus for improving peripheral endothelial function. This study presents novel findings that intermittent elevations in shear rate may be more effective at acutely improving endothelial function compared with continuous elevations. Despite similar increases in total shear rate during handgrip exercise intermittent elevations produced a significantly greater increase in endothelial function when compared with continuous elevations potentially indicating intermittent elevations as a more effective stimulus for acute improvements.

01 Mar 2013·Anti-Cancer Agents in Medicinal ChemistryQ4 · MEDICINE

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

Q4 · MEDICINE

Article

Author: Hochwald, Steven N. ; Magis, Andrew T. ; Ucar, Deniz A. ; He, Di-Hua ; Kurenova, Elena ; Zajac-Kaye, Maria ; Zhang, Jianliang ; Lawrence, Nicholas J. ; Sebti, Said M.

Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In addition, INT2-31 increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.

01 Sep 2012·Cell CycleQ3 · BIOLOGY

Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth

Q3 · BIOLOGY

Article

Author: Said M Sebti ; Audrey Cox ; Steven N Hochwald ; Nicole Massoll ; Nicholas Lawrence ; Deniz A Ucar ; David A Ostrov ; Timothy J Garrett ; Maria Zajac-Kaye ; Elena Kurenova ; William G Cance ; Carl Nyberg

FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	University of Florida	-

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