TY - JOUR
T1 - Factors contributing to the resistance to apoptosis induced by topoisomerase i inhibitors in vincristine resistant cells
AU - Palissot, Valérie
AU - Trussardi, Aurélie
AU - Gorisse, Marie Claude
AU - Dufer, Jean
PY - 1999
Y1 - 1999
N2 - The activity of numerous antineoplasic drugs is correlated with their capacity to induce the apoptotic process. In this study, apoptosis induced by the topoisomerase I (Topo I) inhibitors camptothecin (CPT) and the CPT-11 active metabolite SN-38 was evaluated on HL-60 cells and their multidrug resistant variant HL-60-Vincristine cells. Both CPT and SN-38 induced high levels of apoptosis in sensitive cells but very low levels in MDR cells. The role of the different genes and proteins usually implicated in the drug resistance phenomenon was studied. The Pgp independence of the two drugs was suggested by the lack of modulation of anti-Topo I effects with verapamil. Moreover CPT and SN-38 induced a strong decrease of mdr I mRNA in MDR treated cells. MRP mRNA expression was very low in drug sensitive and resistant cells and decreased during treatments in both cell lines. However, MRP protein was not detected in control and MDR cells suggesting that this pump was probably not implicated in this resistance phenomenon. Topo I and BCL-2 proteins displayed a higher expression in MDR cells but only Topo I proteins decreased during treatments in the two cell lines. These data suggest that in addition to the classical multidrug resistance phenotype, dysregulation of proteins associated with DNA replication and apoptotic process could contribute to acquired resistance to a large panel of drugs, including those which are not considered as substrates for Pgp.
AB - The activity of numerous antineoplasic drugs is correlated with their capacity to induce the apoptotic process. In this study, apoptosis induced by the topoisomerase I (Topo I) inhibitors camptothecin (CPT) and the CPT-11 active metabolite SN-38 was evaluated on HL-60 cells and their multidrug resistant variant HL-60-Vincristine cells. Both CPT and SN-38 induced high levels of apoptosis in sensitive cells but very low levels in MDR cells. The role of the different genes and proteins usually implicated in the drug resistance phenomenon was studied. The Pgp independence of the two drugs was suggested by the lack of modulation of anti-Topo I effects with verapamil. Moreover CPT and SN-38 induced a strong decrease of mdr I mRNA in MDR treated cells. MRP mRNA expression was very low in drug sensitive and resistant cells and decreased during treatments in both cell lines. However, MRP protein was not detected in control and MDR cells suggesting that this pump was probably not implicated in this resistance phenomenon. Topo I and BCL-2 proteins displayed a higher expression in MDR cells but only Topo I proteins decreased during treatments in the two cell lines. These data suggest that in addition to the classical multidrug resistance phenotype, dysregulation of proteins associated with DNA replication and apoptotic process could contribute to acquired resistance to a large panel of drugs, including those which are not considered as substrates for Pgp.
KW - Apoptosis
KW - BCL-2
KW - MRP
KW - Pgp
KW - Resistance
KW - Topoisomerases inhibitors
UR - http://www.scopus.com/inward/record.url?scp=0032619949&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/10500811
U2 - 10.1007/978-1-4615-4811-9_38
DO - 10.1007/978-1-4615-4811-9_38
M3 - Article
C2 - 10500811
AN - SCOPUS:0032619949
SN - 0065-2598
VL - 457
SP - 355
EP - 363
JO - Advances in Experimental Medicine and Biology
JF - Advances in Experimental Medicine and Biology
ER -