Effects of arsenic trioxide (As2O3) on leukemic cells from patients with non-M3 acute myelogenous leukemia: studies of cytotoxicity, apoptosis and the pattern of resistance.
Arsenic oxide (As2O3) has recently been reported to induce remission in a high percentage of patients with acute promyelocytic leukemia (APL). The aim of this study was to investigate the effects of As2O3 at therapeutic concentrations on cell viability and apoptosis on leukemic cells from patients with non-M3 acute myelogenous leukemia (AML) and to study the resistance profile compared to conventional AML drugs. Cells from 20 patients were exposed to therapeutic concentrations of As2O3 continuously for 96 h. As2O3 reduced the viability in blast cells from all the 20 tested patients compared to unexposed controls (p-value: 0.02 at 0.05 microM; <0.005 at 1.0 microM and higher concentrations). An increase in the apoptotic rate was also seen after incubation with As2O3. Parallel to the incubation with arsenic the in vitro sensitivity to a number of chemotherapeutic agents commonly used in AML was studied. Correlation coefficients for the in vitro sensitivity were highly significant between the conventional AML drugs except for Ara-C. For As2O3, all the correlation coefficients were negative and ranged between -0.05 and -0.51. Furthermore, increased P-gp expression in a multidrug resistant HL-60 cell line did not decrease the sensitivity to As2O3 as compared to the parental cell line. Neither did a P-gp-transfected variant of the K562 cell line show decreased sensitivity to As2O3. We conclude that As2O3 at therapeutic concentrations induces apoptosis and cytotoxic effects in blast cells from patients with non-M3 AML, and that As2O3 differs from conventional AML drugs with respect to the mechanisms that confer resistance to the drugs.
Lehmann
S
S
Department of Hematology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden. Soren.Lehmann@medhs.ki.se
Bengtzen
S
S
Paul
A
A
Christensson
B
B
Paul
C
C
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide