High sensitivity of leukemic peripheral blood lymphocytes to triethyllead action.
In a previous study we reported that triethyllead (Et3Pb+) inhibits cell proliferation of normal human lymphocytes. To further characterize this interaction, we studied herein the effects of Et3Pb+ on the cell viability of normal and leukemic human lymphocytes and analysed the expression and dynamics of the monomer/polymer equilibrium of tubulin in these cells. Short- and long-term cell culture experiments demonstrated significantly different dose-dependent effects of Et3Pb+ on cell viability of leukemic compared to normal lymphocytes. Indeed, in the presence of increasing concentrations of Et3Pb+ (10(-12)-10(-5) M), primary cultures of chronic lymphocytes (CLL) and acute lymphoblastic (ALL) leukemic human Lymphocytes were much more sensitive to Et3Pb+ treatment when compared to normal peripheral blood lymphocytes (PBL). The IC50 values were approximately 5 x 10(-6) M for PBL and 8 x 10(-10) M for both CLL and ALL respectively, when cells were preincubated for 3 h with this agent. These experiments revealed a 1000-fold higher responsiveness of leukemic cells to Et3Pb+ treatment. Quantitative immunoblot analysis showed that leukemic cells express up to 4-fold higher total tubulin amounts. However, the proportion of polymerized tubulin in leukemic compared to normal lymphocytes increased only slightly (up to 1.4-fold). These findings reveal a significant decrease in the polymeric to total tubulin ratio in leukemic lymphocytes, indicating important modifications in tubulin dynamics and reorganization of the microtubular structures. Our results demonstrate that leukemic cells are much more sensitive than normal lymphocytes to Et3Pb+ action. This effect may be due to the altered monomer/polymer dynamic equilibrium of tubulin shown in leukemic cells. It is, therefore, worthwhile exploring future applied uses of Et3Pb+ as a potential suppressor of leukemic cell growth.
Stiakaki
E
E
Department of Biochemistry, School of Medicine, University of Crete and the University General Hospital, Heraklion, Greece.
Stournaras
C
C
Dimitriou
H
H
Kalmanti
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D013552:Swine; D014407:Tumor Cells, Cultured
D009942:Organometallic Compounds; C010360:triethyllead