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( Sajita Shah ),( Chaemin Lee ),( Hyukjae Choi ),( Jaya Gautam ),( Hyeonjin Jang ),( Geum Jin Kim ),( Yu Jeong Lee ),( Chhabi Lal Chaudhary ),( Sang Won Park ),( Tae Gyu Nam ),( Jung Ae Kim ),( Byeong 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (sutent®) is an antitumor agent targeting receptor tyrosme kmases which are Involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-01 scaffold. which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinb mimics 6 by hybridizing bicyclic pyridlnol4 as a key scaffold and pyrrole-2-carbaidehydes 7 as side chains, Cytotoxicity assays showed that compounds: 6 have comparable to better anticancer activity than sunltll1lb against five different cancer cell lines. In addition. compounds 6 showed even lower levels of cytotoxicity against normal cells. resulting in up to 26-fold better safety Windows, than sunitinib, Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction In MDA-MB-231 human breast cancer cells by 6F is mall1ly mediated through the pS3 increase and down-regulation of phospho-signal transdu-cer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2. and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with Improved and safer cytotoxicity profiles than sunitinib.
( Sajita Shah ),( Kyu-tae Kang ) 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
Most angiogenesis assays are performed using endothelial cells. However, blood vessels are composed of two cell types: endothelial cells and pericytes. Thus, co-culture of two vascular cells should be employed to evaluate angiogenic properties. Here, we developed an in vitro 3-dimensional angiogenesis assay system using spheroids formed by two human vascular precursors: endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs). ECFCs, MSCs, or ECFCs+MSCs were cultured to form spheroids. Sprout formation from each spheroid was observed for 24 h by real-time cell recorder. Sprout number and length were higher in ECFC+MSC spheroids than ECFC-only spheroids. No sprouts were observed in MSC-only spheroids. Sprout formation by ECFC spheroids was increased by treatment with vascular endothelial growth factor (VEGF) or combination of VEGF and fibroblast growth factor-2 (FGF-2). Interestingly, there was no further increase in sprout formation by ECFC+MSC spheroids in response to VEGF or VEGF+FGF-2, suggesting that MSCs stimulate sprout formation by ECFCs. Immuno-fluorescent labeling technique revealed that MSCs surrounded ECFC-mediated sprout structures. We tested vatalanib, VEGF inhibitor, using ECFC and ECFC+MSC spheroids. Vatalanib significantly inhibited sprout formation in both spheroids. Of note, the IC<sub>50</sub> of vatalanib in ECFC+MSC spheroids at 24 h was 4.0 ± 0.40 µM, which are more correlated with the data of previous animal studies when compared with ECFC spheroids (0.2 ± 0.03 µM). These results suggest that ECFC+MSC spheroids generate physiologically relevant sprout structures composed of two types of vascular cells, and will be an effective pre-clinical in vitro assay model to evaluate pro- or anti-angiogenic property.
Shah, Sajita,Kang, Kyu-Tae The Korean Society of Applied Pharmacology 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
Most angiogenesis assays are performed using endothelial cells. However, blood vessels are composed of two cell types: endothelial cells and pericytes. Thus, co-culture of two vascular cells should be employed to evaluate angiogenic properties. Here, we developed an in vitro 3-dimensional angiogenesis assay system using spheroids formed by two human vascular precursors: endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs). ECFCs, MSCs, or ECFCs+MSCs were cultured to form spheroids. Sprout formation from each spheroid was observed for 24 h by real-time cell recorder. Sprout number and length were higher in ECFC+MSC spheroids than ECFC-only spheroids. No sprouts were observed in MSC-only spheroids. Sprout formation by ECFC spheroids was increased by treatment with vascular endothelial growth factor (VEGF) or combination of VEGF and fibroblast growth factor-2 (FGF-2). Interestingly, there was no further increase in sprout formation by ECFC+MSC spheroids in response to VEGF or VEGF+FGF-2, suggesting that MSCs stimulate sprout formation by ECFCs. Immuno-fluorescent labeling technique revealed that MSCs surrounded ECFC-mediated sprout structures. We tested vatalanib, VEGF inhibitor, using ECFC and ECFC+MSC spheroids. Vatalanib significantly inhibited sprout formation in both spheroids. Of note, the $IC_{50}$ of vatalanib in ECFC+MSC spheroids at 24 h was $4.0{\pm}0.40{\mu}M$, which are more correlated with the data of previous animal studies when compared with ECFC spheroids ($0.2{\pm}0.03{\mu}M$). These results suggest that ECFC+MSC spheroids generate physiologically relevant sprout structures composed of two types of vascular cells, and will be an effective pre-clinical in vitro assay model to evaluate pro- or anti-angiogenic property.
( Sushil C Regmi ),( Su Young Park ),( Seung Joo Kim ),( Suhrid Banskota ),( Sajita Shah ),( Dong Hee Kim ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7 -O-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-eaten in destruction complex, which was achieved through inhibition of regulatory compo-nents associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC<sub>50</sub> of 50.1 IJM and 15.51JM for tankyrase 1 and 2, respectively) compared to XAV939 (IC<sub>50</sub> of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TGF/LEF1 transcriptional activity (IC<sub>50</sub> of 39.8 nM), which were similar to that of XAV939 (IC<sub>50</sub> of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells in vitro, SMA significantly inhibited tumor growth in GT26 syngenic and HT29 xenograft mouse tumor models. Furthennore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phos-phorylation and increases in axin levels. These results suggest that SMA is a possible can-didate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the β-catenin destruction complex through inhibition of tankyrase and the PI3K/Akt signaling pathway.