Doxycycline induces apoptosis in PANC-1 pancreatic cancer cells.
BACKGROUND
Tetracyclines such as doxycycline are reported to possess cytotoxic activity against mammalian tumor cells, but the mechanism of their effects on cell proliferation remains unclear.


METHODS
The antitumor effect of doxycycline was investigated in human pancreatic cancer cell line, PANC-1. We also investigated the effect of doxycycline on expression of a potent proangiogenic factor, interleukin (IL)-8.


RESULTS
In excess of 20 microg/ml, cytotoxic effects of doxycycline were accompanied by G(1)-S cell cycle arrest and DNA fragmentation in PANC-1 cells. Doxycycline consistently activated transcription of p53, p21 and Fas/FasL-cascade-related genes, while reducing the expression of Bcl-xL and Mcl-1. Doxycycline (5 microg/ml) below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. In the mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by 80%.


CONCLUSIONS
These data suggest that doxycycline exerts its antitumor effect by activating proapoptotic genes, inhibiting IL-8 expression, and suppressing antiapoptotic genes.
Son
Kyonsu
K
Department of Surgery, Jikei University Hospital, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. son@jikei.ac.jp
Fujioka
Shuichi
S
Iida
Tomonori
T
Furukawa
Kenei
K
Fujita
Tetsuji
T
Yamada
Hisashi
H
Chiao
Paul J
PJ
Yanaga
Katsuhiko
K
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology*; D004347:Drug Interactions; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016196:S Phase / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004318:Doxycycline; D017239:Paclitaxel