TY - JOUR
T1 - Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation
AU - González-Sánchez, Ignacio
AU - Solano, José D.
AU - Loza-Mejía, Marco A.
AU - Olvera-Vázquez, Susana
AU - Rodríguez-Sotres, Rogelio
AU - Morán, Julio
AU - Lira-Rocha, Alfonso
AU - Cerbón, Marco A.
N1 - Funding Information:
This work was supported in part by the DGAPA ( IN202805 ) and the Instituto de Ciencia y Tecnología del Distrito Federal , México, D.F. México. Thanks are due to Bruce Allan Larsen for reviewing the use of English in this manuscript. Dra. C. Adriana Mendoza Rodríguez contributed during experimental procedures and manuscript preparation.
PY - 2011/6
Y1 - 2011/6
N2 - Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b] quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.
AB - Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b] quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.
KW - 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b] quinoline (D3CLP)
KW - Anti-tumor activity
KW - Cell death
KW - Effector caspases
KW - K-562 cells
UR - http://www.scopus.com/inward/record.url?scp=79955608057&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2011.02.063
DO - 10.1016/j.ejmech.2011.02.063
M3 - Artículo
SN - 0223-5234
VL - 46
SP - 2102
EP - 2108
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 6
ER -