TY - JOUR
T1 - Multidrug reverting activity toward leukemia cells in a group of new verapamil analogues with low cardiovascular activity.
AU - Biscardi, Monica
AU - Teodori, Elisabetta
AU - Caporale, Roberto
AU - Budriesi, Roberta
AU - Balestri, Francesca
AU - Scappini, Barbara
AU - Gavazzi, Sabrina
N1 - Keywords: Adult; Aged; Aged, 80 and over; Animals; Anti-Arrhythmia Agents; Antibiotics, Antineoplastic; Aorta; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Guinea Pigs; Heart Atria; Humans; Idarubicin; K562 Cells; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Organ Culture Techniques; P-Glycoprotein; Verapamil
PY - 2005
Y1 - 2005
N2 - The development of refractory disease is often associated with the overexpression of multidrug resistance (MDR) proteins, especially in several hematological malignancies, such as acute myeloid leukemias (AML), multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). Since the recognition of these proteins, several attempts have been made to modulate their expression and activity (protein kinase C inhibitors, anti-MDR-1 oligonucleotides, pharmacological competitors and transcriptional inhibitors). Six new compounds (MM 36, CTS 4, CTS 9, CTS 12, CTS 27 and CTS 41), derived from verapamil (VRP), were designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein-acetoxymethyl (Calcein-AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML. Furthermore, the six molecules were tested for their vasodilator, inotropic and chronotropic activity on guinea pig aortic strip and isolated atrium preparations, respectively. Comparison between survival plots and relative ID50, obtained from the K-562/doxR cells treated with Idarubicin (IDA), in the presence or absence of inhibitors, showed that these compounds function well. All the resistance modifying agents potentiated IDA activity inducing a significant reduction (P<0.01) in ID(50) values in comparison to VRP at each of the concentrations tested, but MM 36, CTS 27 and CTS 41 demonstrated the strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36>CTS 27>CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP analogues. Compared to VRP, all the new compounds presented good MDR-reverting- and reduced cardiovascular activities along with no vasorelaxant effects. The particularly favourable results in some cases (MM 36, CTS 27 and CTS 41) suggests that anti-MDR activity should be further evaluated in clinical trials in patients with myeloid malignancies.
AB - The development of refractory disease is often associated with the overexpression of multidrug resistance (MDR) proteins, especially in several hematological malignancies, such as acute myeloid leukemias (AML), multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). Since the recognition of these proteins, several attempts have been made to modulate their expression and activity (protein kinase C inhibitors, anti-MDR-1 oligonucleotides, pharmacological competitors and transcriptional inhibitors). Six new compounds (MM 36, CTS 4, CTS 9, CTS 12, CTS 27 and CTS 41), derived from verapamil (VRP), were designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein-acetoxymethyl (Calcein-AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML. Furthermore, the six molecules were tested for their vasodilator, inotropic and chronotropic activity on guinea pig aortic strip and isolated atrium preparations, respectively. Comparison between survival plots and relative ID50, obtained from the K-562/doxR cells treated with Idarubicin (IDA), in the presence or absence of inhibitors, showed that these compounds function well. All the resistance modifying agents potentiated IDA activity inducing a significant reduction (P<0.01) in ID(50) values in comparison to VRP at each of the concentrations tested, but MM 36, CTS 27 and CTS 41 demonstrated the strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36>CTS 27>CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP analogues. Compared to VRP, all the new compounds presented good MDR-reverting- and reduced cardiovascular activities along with no vasorelaxant effects. The particularly favourable results in some cases (MM 36, CTS 27 and CTS 41) suggests that anti-MDR activity should be further evaluated in clinical trials in patients with myeloid malignancies.
U2 - 10.1016/j.leukres.2005.06.005
DO - 10.1016/j.leukres.2005.06.005
M3 - Journal article
C2 - 16061283
SN - 0145-2126
VL - 30
SP - 1
EP - 8
JO - Leukemia Research
JF - Leukemia Research
IS - 1
ER -