Enhancement of adriamycin cytotoxicity by sodium butyrate involves hTERT downmodulation-mediated apoptosis in human uterine cancer cells.
Activation of telomerase is a key element in oncogenesis and resistance to apoptosis for many cancers. Some histone deacetylase inhibitors (HDACi) or chemotheraputic agents have been reported to downregulate the expression of human telomerase reverse transcriptase (hTERT). However, whether hTERT is involved in cell death of uterine cancer cells induced by combination of HDACi with chemotheraputic regents remain unknown. The present study shows that combining sodium butyrate (NaBu) and adriamycin (ADR) inhibits proliferation of uterine cancer cell lines in a concentration and time-dependent manner. Growth inhibition was accompanied by caspase-dependent apoptosis with reduced telomerase activity and decreased hTERT mRNA expression. Ectopic wild type (WT)-hTERT suppressed the apoptosis induced by NaBu/ADR treatment, while knockdown of hTERT sensitized uterine cancer cells to ADR. Moreover, the addition of NaBu significantly enhanced ADR cytotoxicity for the primary uterine cancer cells with high hTERT expression. These data indicate that downregulation of hTERT is an important part of the mechanism by which NaBu enhances ADR-induced apoptosis, and suggests that combining NaBu and ADR may be effective in treating uterine tumor with high telomerase activity.
Key Laboratory of Transgenetic Animal Research, Liaoning Province, Department of Laboratory Animal, China Medical University, Shenyang, China.
Meng
M
Yu
Hong
H
Kong
Yan
Y
Zhao
Xuefei
X
Sun
Zhihong
Z
Zheng
Chunming
C
Yang
Yuyan
Y
Zhu
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020148:Butyric Acid / Q000494:pharmacology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006633:Histamine Antagonists / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D006633:Histamine Antagonists; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020148:Butyric Acid; D004317:Doxorubicin; C509186:TERT protein, human; D019098:Telomerase; D053181:Caspase 8; D053453:Caspase 9
adriamycin; hTERT; ovarian cancer; sodium butyrate; telomerase