Tumor selectivity and transcriptional activation by azelaic bishydroxamic acid in human melanocytic cells.
Azelaic bishydroxamic acid (ABHA), a potent differentiating agent for lymphoid cells, was selectively toxic for 5 human tumor cell lines and transformed human melanocytes and keratinocytes (dose for 37% survival, D37, 30-100 microg/mL) compared with normal cells (melanocytes, fibroblasts; D37 > 300 microg/mL). Dendritic morphology was the only indicator found for increased differentiation, markers for the pigmentation pathway being unchanged or inhibited by ABHA. In contrast to hexamethylene bisacetamide and azelaic acid, ABHA significantly increased the HIV LTR, SV40 and c-fos promoter activities during a 24 hr treatment. Metallothionein promoter activity was enhanced by 5 hr treatment with ABHA in a sensitive melanoma cell line (MM96L) but was inhibited in a more resistant line (HeLa); c-fos promoter activity was inhibited in HeLa during this time. Transcription from a p53 binding response element was inhibited in MM96L by a 24 hr ABHA treatment but enhanced in HeLa. ABHA may represent a structural prototype for designing more potent and selective anti-melanoma agents.
Parsons
P G
PG
Queensland Cancer Fund Laboratories, Queensland Institute of Medical Research, Herston, Australia.
Hansen
C
C
Fairlie
D P
DP
West
M L
ML
Danoy
P A
PA
Sturm
R A
RA
Dunn
I S
IS
Pedley
J
J
Ablett
E M
EM
D000081:Acetamides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D007370:Interferon Type I / Q000032:analysis; D008544:Melanocytes / Q000187:drug effects*; D008562:Membrane Glycoproteins; D014442:Monophenol Monooxygenase / Q000032:analysis; D010088:Oxidoreductases; D011506:Proteins / Q000032:analysis; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000081:Acetamides; D000970:Antineoplastic Agents; D003998:Dicarboxylic Acids; D006877:Hydroxamic Acids; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D011506:Proteins; C107648:azelaic bishydroxamic acid; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; C010038:azelaic acid; C014026:hexamethylene bisacetamide