Induction of DNA fragmentation in human myelogenous leukaemic cell lines by phenothiazine-related compounds.
A series of phenothiazine, benzo[a]phenothiazine and benz[c]acridine derivatives were compared for their ability to induce nucleosome-sized DNA fragmentation (a biochemical hallmark of apoptosis), using agarose gel electrophoresis and a fluorescence activated cell sorter. Significant DNA fragmentation-inducing activity was detected in 12H-benzo[a]phenothiazine, 5-oxo-5H-benzo[a]phenothiazine and 9-methyl-12H-benzo[a]phenothiazine, which induced the monocytic differentiation of human myelogenous leukaemic cell lines. On the other hand, an other three benzo[a]phenothiazines, six 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, six 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas, and twelve benz[c]acridines showed little or no DNA fragmentation-inducing activity. Active benzo[a]phenothiazines induced DNA fragmentation in four human myelogenous leukaemic cell lines (HL-60, ML-1, U-937, THP-1), but not in human T-cell leukaemic MOLT-4 and erythroleukaemic K-562 cell lines, which were also resistant to other apoptosis-inducing agents. Ca2+-depletion from the culture medium did not significantly affect their DNA fragmentation-inducing activity. The differentiation and apoptosis-inducing activity of benzo[a]phenothiazines have an important role for their medicinal efficacy.
Sakagami
H
H
First Department of Biochemistry, School of Medicine, Showa University, Tokyo, Japan.
Takahashi
H
H
Yoshida
H
H
Yamamura
M
M
Fukuchi
K
K
Gomi
K
K
Motohashi
N
N
Takeda
M
M
D000166:Acridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis*; D004587:Electrophoresis, Agar Gel; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D015394:Molecular Structure; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D010640:Phenothiazines; C035985:benz(c)acridine; D002118:Calcium