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18 results on '"Saengsawang, Witchuda"'

10. Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide

Author

Monger, Adeep, Boonmuen, Nittaya, Suksen, Kanoknetr, Saeeng, Rungnapha, Kasemsuk, Teerapich, Piyachaturawat, Pawinee, Saengsawang, Witchuda, and Chairoungdua, Arthit

Subjects
topoisomerase IIα, inhibitors, apoptosis, DNA damage, andrographolide analogue, Gastric cancer, Research Article
Abstract

Gastric cancer is the most common cancer in Eastern Asia. Increasing chemoresistance and general systemic toxicities have complicated the current chemotherapy leading to an urgent need of more effective agents. The present study reported a potent DNA topoisomerase IIα inhibitory activity of an andrographolide analogue (19-triisopropyl andrographolide, analogue-6) in gastric cancer cells; MKN-45, and AGS cells. The analogue was potently cytotoxic to both gastric cancer cell lines with the half maximal inhibitory concentration (IC50 values) of 6.3±0.7 μM, and 1.7±0.05 μM at 48 h for MKN-45, and AGS cells, respectively. It was more potent than the parent andrographolide and the clinically used, etoposide with the IC50 values of >50 μM in MKN-45 and 11.3±2.9 μM in AGS cells for andrographolide and 28.5±4.4 μM in MKN-45 and 4.08±0.5 μM in AGS cells for etoposide. Analogue-6 at 2 μM significantly inhibited DNA topoisomerase IIα enzyme in AGS cells, induced DNA damage, activated cleaved PARP-1, and Caspase3 leading to late cellular apoptosis. Interestingly, the expression of tumor suppressor p53 was not activated. These results show the importance of 19-triisopropyl-andrographolide in its emerging selectivity to primary target on topoisomerase IIα enzyme, inducing DNA damage and apoptosis by p53- independent mechanism. Thereby, the results provide insights of the potential of 19-triisopropyl andrographolide as an anticancer agent for gastric cancer. The chemical transformation of andrographolide is a promising strategy in drug discovery of a novel class of anticancer drugs from bioactive natural products.

Published
2017

18. Synaptic Regulation of Microtubule Dynamics in Dendritic Spines by Calcium, F-Actin, and Drebrin.

Author

Merriam, Elliott B., Millette, Matthew, Lumbard, Derek C., Saengsawang, Witchuda, Fothergill, Thomas, Xindao Hu, Ferhat, Lotfi, and Dent, Erik W.

Subjects
NEUROPLASTICITY, MICROTUBULES, DENDRITIC cells, F-actin, METHYL aspartate receptors, LABORATORY mice
Abstract

Dendritic spines are actin-rich compartments that protrude from the microtubule-rich dendritic shafts of principal neurons. Spines contain receptors and postsynaptic machinery for receiving the majority of glutamatergic inputs. Recent studies have shown that microtubules polymerize from dendritic shafts into spines and that signaling through synaptic NMDA receptors regulates this process. However, the mechanisms regulating microtubule dynamics in dendrites and spines remain unclear. Here we show that in hippocampal neurons from male and female mice, the majority of microtubules enter spines from highly localized sites at the base of spines. These entries occur in response to synapse-specific calcium transients that promote microtubule entry into active spines. We further document that spine calcium transients promote local actin polymerization, and that F-actin is both necessary and sufficient for microtubule entry. Finally, we show that drebrin, a protein known to mediate interactions between F-actin and microtubules, acts as a positive regulator of microtubule entry into spines. Together these results establish for the first time the essential mechanisms regulating microtubule entry into spines and contribute importantly to our understanding of the role of microtubules in synaptic function and plasticity. [ABSTRACT FROM AUTHOR]

Published
2013
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