Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells.
OBJECTIVE
The induction of polyamine catabolism has been directly associated with the cytotoxic response of various tumor types to the antitumor polyamine analogues. Initially, human polyamine catabolism was assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO). We have recently cloned a new polyamine analogue-inducible human polyamine oxidase (PAOh1/SMO) that efficiently uses spermine as a substrate. The induction of PAOh1/SMO in response to multiple polyamine analogues was examined in representative lung tumor cell lines.


METHODS
Representatives of three different classes of antitumor polyamine analogues were examined for their ability to induce PAOh1/SMO.


RESULTS
The human adenocarcinoma line, NCI A549 was found to be the most responsive line with respect to induction of PAOh1/SMO in response to analogue exposure. Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines. Using a series of polyamine analogues, it was found that the most potent inducers of PAOh1/SMO possessed multiple three-carbon linkers between nitrogens, as typified by N1,N11-bis(ethyl)norspermine.


CONCLUSIONS
Since PAOh1/SMO is an analogue-inducible enzyme that produces H2O2 as a metabolic product, it may play a significant role in determining the sensitivity of various human tumors to specific polyamine analogues.
Devereux
Wendy
W
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Wang
Yanlin
Y
Stewart
Tracy Murray
TM
Hacker
Amy
A
Smith
Renee
R
Frydman
Benjamin
B
Valasinas
Aldonia L
AL
Reddy
Venodhar K
VK
Marton
Laurence J
LJ
Ward
Tracey D
TD
Woster
Patrick M
PM
Casero
Robert A
RA
D000123:Acetyltransferases / Q000378:metabolism; D015152:Blotting, Northern; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D018288:Carcinoma, Small Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000096:biosynthesis*; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013379:Substrate Specificity; D013997:Time Factors; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D012333:RNA, Messenger; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase