Differanisole A, a novel antitumor antibiotic, enhances growth inhibition and differentiation of human myeloid leukemia cells induced by 9-cis retinoic acid.
Differanisole A, 3,5-dichloro-2-hydroxy-4-methoxy-6-n-propylbenzoic acid, inhibited growth of human myeloid leukemia cells. The compound induced G1 arrest and granulocytic differentiation of HL-60 cells, although the differentiation-inducing effect was modest. Differanisole A and 9-cis retinoic acid (9cisRA) synergistically inhibited the growth and induced functional and morphologic differentiation of HL-60 and NB4 cells, whereas the combined treatment with differanisole A and all-trans retinoic acid or 1alpha,25-dihydroxyvitamin D3 was less effective. Similar results were obtained in primary culture of leukemia cells from a patient with acute promyelocytic leukemia. The synergistic effect on growth inhibition and induction of differentiation required simultaneous treatment with differanisole A and 9cisRA. Differanisole A and an RXR-specific ligand (Ro47-5944) cooperatively inhibited the cell growth, while the combined effect of differanisole A and an RAR-specific ligand Am80 was just additive. Differanisole A in combination with 9cisRA may have implications for therapy of acute promyelocytic leukemia patients.
Kanatani
Y
Y
Department of Chemotherapy, Saitama Cancer Center Research Institute, Ina, Japan.
Makishima
M
M
Asahi
K
K
Sakurai
A
A
Takahashi
N
N
Motoyoshi
K
K
Nagata
N
N
Honma
Y
Y
D000077556:Alitretinoin; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002723:Chlorobenzoates / Q000494:pharmacology*; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008024:Ligands; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D002723:Chlorobenzoates; D008024:Ligands; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013778:Tetrazolium Salts; D000077556:Alitretinoin; D014212:Tretinoin; C046689:differanisole A; D002117:Calcitriol