ABSTRACT
The major problem in the treatment of acute myeloid leukemia (AML) patients results from multidrug resistance to administered anticancer agents. Drug resistance proteins, MDR1 and MRP1, which work as drug efflux pumps, can mediate the multidrug resistance of human leukemia cells. In this study, the mechanisms of resistance to doxorubicin-induced cell death in human HL60 AML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of doxorubicin resulted in the selection of HL60/DOX cells, which expressed about 10.7-fold resistance as compared to parental sensitive cells. The expression analyses of MRP1 and MDR1 drug efflux proteins in doxorubicin-sensitive and -resistant HL60 cells revealed that there was an upregulation of MRP1 gene in HL60/DOX cells as compared to parental sensitive cells. On the other hand, while there was no expression of MDR1 gene in parental cells, the expression of MDR1 gene was upregulated in HL60/DOX cells. HL60/DOX cells also showed cross-resistance to cytosine arabinoside (Ara-c). This resistance was reversed by a combination therapy of Ara-c and cyclosporine A. However, the expression levels of CD15 and CD16 surface markers were significantly decreased in HL60/DOX cells.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Doxorubicin/pharmacokinetics , Drug Resistance, Multiple/genetics , Leukemia, Myeloid, Acute/drug therapy , Multidrug Resistance-Associated Proteins/genetics , Cyclosporine/pharmacokinetics , Cytarabine/pharmacokinetics , Drug Resistance, Multiple/drug effects , Drug Therapy, Combination , HL-60 Cells , Humans , Leukemia, Myeloid, Acute/pathology , Lewis X Antigen , Receptors, IgG , Up-Regulation/geneticsABSTRACT
Tumor cells have the capacity to proliferate indefinitely that is qualified as replicative immortality. This ability contrasts with the intrinsic control of the number of cell divisions in human somatic tissues by a mechanism called replicative senescence. Replicative immortality is acquired by inactivation of p53 and p16INK4a genes and reactivation of hTERT gene expression. It is unknown whether the cancer cell replicative immortality is reversible. Here, we show the spontaneous induction of replicative senescence in p53-and p16INK4a-deficient hepatocellular carcinoma cells. This phenomenon is characterized with hTERT repression, telomere shortening, senescence arrest, and tumor suppression. SIP1 gene (ZFHX1B) is partly responsible for replicative senescence, because short hairpin RNA-mediated SIP1 inactivation released hTERT repression and rescued clonal hepatocellular carcinoma cells from senescence arrest.
