Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.yexcr.2018.06.029
Title: SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling
Authors: Seah, Kwi Shan 
Loh, Jian Yun 
Thi, Thuy Trang Nguyena
Hwei, Ling Tan 
Hutchinson, Paul E 
Lim, Kim Kiat 
Dymock, Brian W 
Long, Yun Chau 
Lee Jon Deoon,Edmund 
Shen, Han-Ming 
Chen, Ee Sin 
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
Doxorubicin
SAHA
AMPK
MTOR
Synthetic lethality
Gastric cancer
ACTIVATED PROTEIN-KINASE
STRAND BREAK REPAIR
SYNTHETIC LETHALITY
CHROMATIN-STRUCTURE
H4-K16 ACETYLATION
MAMMALIAN TARGET
RAPAMYCIN MTOR
FISSION YEAST
BRCT DOMAINS
HISTONE
Issue Date: 15-Sep-2018
Publisher: ELSEVIER INC
Citation: Seah, Kwi Shan, Loh, Jian Yun, Thi, Thuy Trang Nguyena, Hwei, Ling Tan, Hutchinson, Paul E, Lim, Kim Kiat, Dymock, Brian W, Long, Yun Chau, Lee Jon Deoon,Edmund, Shen, Han-Ming, Chen, Ee Sin (2018-09-15). SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling. EXPERIMENTAL CELL RESEARCH 370 (2) : 283-291. ScholarBank@NUS Repository. https://doi.org/10.1016/j.yexcr.2018.06.029
Abstract: Chemotherapy remains the most prescribed anti-cancer therapy, despite patients suffering severe side effects and frequently developing chemoresistance. These complications can be partially overcome by combining different chemotherapeutic agents that target multiple biological pathways. However, selecting efficacious drug combinations remains challenging. We previously used fission yeast Schizosaccharomycespombe as a surrogate model to predict drug combinations, and showed that suberoylanilide hydroxamic acid (SAHA) and cisplatin can sensitise gastric adenocarcinoma cells toward the cytotoxic effects of doxorubicin. Yet, how this combination undermines cell viability is unknown. Here, we show that SAHA and doxorubicin markedly enhance the cleavage of two apoptosis markers, caspase 3 and poly-ADP ribose polymerase (PARP-1), and increase the phosphorylation of γH2AX, a marker of DNA damage. Further, we found a prominent reduction in Ser485 phosphorylation of AMP-dependent protein kinase (AMPK), and reductions in its target mTOR and downstream ribosomal protein S6 phosphorylation. We show that SAHA contributes most of the effect, as confirmed using another histone deacetylase inhibitor, trichostatin A. Overall, our results show that the combination of SAHA and doxorubicin can induce apoptosis in gastric adenocarcinoma in a synthetically lethal manner, and that fission yeast offers an efficient tool for identifying potent drug combinations against human cancer cells.
Source Title: EXPERIMENTAL CELL RESEARCH
URI: https://scholarbank.nus.edu.sg/handle/10635/239188
ISSN: 0014-4827
1090-2422
DOI: 10.1016/j.yexcr.2018.06.029
Appears in Collections:Staff Publications
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