NSC746364, a G-quadruplex-stabilizing agent, suppresses cell growth of A549 human lung cancer cells through activation of the ATR/Chk1-dependent pathway.
The telomere is considered to be a potential target for cancer therapy. NSC746364, a novel G-quadruplex-stabilizing agent, has been found to have cytotoxic effects on various cancer cells. To date, its pharmacological mechanisms are still unknown. The goal of this study was to investigate the molecular mechanisms of NSC746364 on the A549 human lung adenocarcinoma cell line. For this, we used a wide variety of in vitro assays. The intracellular signaling pathways including DNA damage sensing and response proteins, cell cycle regulatory proteins, and some key executors involved in apoptosis were evaluated in this study. Our study suggested that NSC746364 induced cell cycle arrest at the G2/M phase and triggers programming cell death on A549 human lung cancer cells, whose effects are modulated through the activation of the ATR/Chk1 pathway, the downregulation of cyclin B1 expression, and the activation of caspase-3. Consequently, our results indicated that NSC746364 may have therapeutic potential as a chemotherapy for non-small-cell lung cancers.
School of Pharmacy, China Medical University, Taiwan.
Yun-Lung
YL
Chung
Chun-Hsu
CH
Pan
Wei-Hung
WH
Liou
Ming-Jyh
MJ
Sheu
Wen-Hsin
WH
Lin
Tsung-Chih
TC
Chen
Hsu-Shan
HS
Huang
Chieh-Hsi
CH
Wu
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D056744:Cyclin B1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D058990:Molecular Targeted Therapy; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000502:physiology*
D000880:Anthraquinones; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; C547438:NSC746364; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019098:Telomerase; D053148:Caspase 3