Inhibition of human class 3 aldehyde dehydrogenase, and sensitization of tumor cells that express significant amounts of this enzyme to oxazaphosphorines, by chlorpropamide analogues.
In some cases, acquired as well as constitutive tumor cell resistance to a group of otherwise clinically useful antineoplastic agents collectively referred to as oxazaphosphorines, e.g. cyclophosphamide and mafosfamide, can be accounted for by relatively elevated cellular levels of an enzyme, viz. cytosolic class 3 aldehyde dehydrogenase (ALDH-3), that catalyzes their detoxification. Ergo, inhibitors of ALDH-3 could be of clinical value since their inclusion in the therapeutic protocol would be expected to sensitize such cells to these agents. Identified in the present investigation were two chlorpropamide analogues showing promise in that regard, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester (NPI-2) and 4-chloro-N-methoxy-N-[(propylamino)carbonyl]benzenesulfonamide (API-2). Each inhibited NAD-linked benzaldehyde oxidation catalyzed by ALDH-3s purified from human breast adenocarcinoma MCF-7/0/CAT cells (IC50 values were 16 and 0.75 microM, respectively) and human normal stomach mucosa (IC50 values were 202 and 5 microM, respectively). The differential sensitivities of stomach mucosa ALDH-3 and breast tumor ALDH-3 to each of the two inhibitors can be viewed as further evidence that the latter is a subtle variant of the former. Human class 1 (ALDH-1) and class 2 (ALDH-2) aldehyde dehydrogenases were much less sensitive to NPI-2; IC50 values were >300 microM in each case. API-2, however, did not exhibit a similar degree of specificity; IC50 values for ALDH-1 and ALDH-2 were 7.5 and 0.08 microM, respectively. Each sensitized MCF-7/0/CAT cells to mafosfamide; the LC90 value decreased from >2 mM to 175 and 200 microM, respectively. Thus, the therapeutic potential of combining NPI-2 or API-2 with oxazaphosphorines is established.
Rekha
G K
GK
Department of Pharmacology, University of Minnesota Health Sciences Center, Minneapolis 55455, USA.
Devaraj
V R
VR
Sreerama
L
L
Lee
M J
MJ
Nagasawa
H T
HT
Sladek
N E
NE
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002219:Carbamates / Q000494:pharmacology*; D002747:Chlorpropamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000444:Aldehyde Dehydrogenase; D000970:Antineoplastic Agents; D002219:Carbamates; D002747:Chlorpropamide; D003520:Cyclophosphamide; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C111224:API 2; D000096926:Benzenesulfonamides; C111225:NPI 2; C030863:corneal protein 54, bovine; C048341:mafosfamide