The effects of microtubule disrupting drugs on the differentiation of HL-60 leukemia cells.
We and others have previously shown that microtubules (MT) are stained more intensely and are organized differently in differentiating leukemia cells. To study the effects of the MT disrupting drugs, colchicine (Coln) and vincristine (VCR), on the maturation process, HL-60 leukemia cells were pretreated with Coln or VCR for 1 h and then exposed to either retinoic acid (RA) or dimethyl sulfoxide (DMSO). Neither Coln nor VCR induced the differentiation of HL-60 cells, but in combination with RA increased the percentage of nitroblue tetrazolium-positive cells, the expression of the mature myelocyte surface marker Mo 1, and the content of MT over the effects produced by RA alone. In contrast, pretreatment with Coln or VCR delayed the commitment to a differentiation pathway induced by DMSO. The supra-additivity exhibited between Coln and RA required the administration of Coln prior to RA; thus, Coln had no effect when given two days after the cellular exposure to RA. The findings suggest that (a) a combination of non-cytotoxic concentrations of Coln or VCR with RA may have clinical utility as inducers of leukemia cell maturation, and (b) MT may be involved in modulating signal transduction during the initiation of HL-60 cell differentiation.
Leung
M F
MF
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
Sartorelli
A C
AC
D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D008870:Microtubules / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D014212:Tretinoin; D014750:Vincristine; D003078:Colchicine; D004121:Dimethyl Sulfoxide