Hydroxylamine-containing inhibitors of polyamine biosynthesis and impairment of colon cancer cell growth.
Polyamine synthesis (by the action of ornithine decarboxylase [ODC] and S-adenosylmethionine decarboxylase [SAMDC]) and polyamine content are high in colon cancer. In addition, colonic lumen is rich in polyamines synthesised by colonic microflora; for this reason, polyamine depletion in colon cancer may be a logical approach to impair growth of colon cancer cells. We evaluated highly specific and reportedly non-toxic hydroxylamine-containing inhibitors of ODC (1-aminooxy-3-aminopropane, APA) and SAMDC (S-(5'-deoxy-5'-adenosyl)-methylthioethyl-hydroxylamine, AMA) in human colon cancer cells (Caco-2 and HT-29) in culture. APA depleted ODC activity within 24 hr, more rapidly than did difluoromethylornithine. APA and AMA in combination (100 microM each) reduced ODC and SAMDC activities to undetectable levels within 24 hr and intracellular polyamines to 8-23% of control. The resulting growth arrest could be reversed only by twice as much spermidine as is physiologically present in the colonic lumen. In concentrations sufficient to deplete growth, APA and AMA were not toxic. Simultaneous treatment with APA, AMA, and 5-fluorouracil reduced colon cancer cell survival more potently than treatment with 5-fluorouracil alone. The hydroxylamine-containing ODC and SAMDC inhibitors APA and AMA are potent inhibitors of colon cancer cell proliferation and might be therapeutically promising in colon cancer.
Milovica
V
V
2nd Department of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany. Milovic@em.uni-frankfurt.de
Turchanowa
L
L
Khomutov
A R
AR
Khomutov
R M
RM
Caspary
W F
WF
Stein
J
J
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003839:Deoxyadenosines / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000037:antagonists & inhibitors*; D011437:Propylamines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D006898:Hydroxylamines; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011437:Propylamines; C042768:S-(5'-deoxyadenosyl-5')-S-methylthioethylhydroxylamine; C046252:1-aminooxy-3-aminopropane; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D005472:Fluorouracil