Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation

Ignacio González-Sánchez, José D. Solano, Marco A. Loza-Mejía, Susana Olvera-Vázquez, Rogelio Rodríguez-Sotres, Julio Morán, Alfonso Lira-Rocha, Marco A. Cerbón

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Abstract

Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalat es 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. © 2011 Elsevier Masson SAS.
Original languageAmerican English
Pages (from-to)2102-2108
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
DOIs
StatePublished - 1 Jun 2011
Externally publishedYes

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Effector Caspases
Cell death
Antineoplastic Agents
Chemical activation
Derivatives
Cell Death
Flow cytometry
Cells
Tumors
Amsacrine
Quinolines
Pharmaceutical Preparations
Flow Cytometry
Leukemia
Type II DNA Topoisomerase
Fluorometry
Cytotoxicity
In Situ Nick-End Labeling
Chromatin
Condensation

Cite this

González-Sánchez, Ignacio ; Solano, José D. ; Loza-Mejía, Marco A. ; Olvera-Vázquez, Susana ; Rodríguez-Sotres, Rogelio ; Morán, Julio ; Lira-Rocha, Alfonso ; Cerbón, Marco A. / Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation. In: European Journal of Medicinal Chemistry. 2011 ; pp. 2102-2108.
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abstract = "Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalat es 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. {\circledC} 2011 Elsevier Masson SAS.",
author = "Ignacio Gonz{\'a}lez-S{\'a}nchez and Solano, {Jos{\'e} D.} and Loza-Mej{\'i}a, {Marco A.} and Susana Olvera-V{\'a}zquez and Rogelio Rodr{\'i}guez-Sotres and Julio Mor{\'a}n and Alfonso Lira-Rocha and Cerb{\'o}n, {Marco A.}",
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Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation. / González-Sánchez, Ignacio; Solano, José D.; Loza-Mejía, Marco A.; Olvera-Vázquez, Susana; Rodríguez-Sotres, Rogelio; Morán, Julio; Lira-Rocha, Alfonso; Cerbón, Marco A.

In: European Journal of Medicinal Chemistry, 01.06.2011, p. 2102-2108.

Research output: Contribution to journalArticleResearchpeer-review

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.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalat es 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. © 2011 Elsevier Masson SAS.

AB - Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalat es 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. © 2011 Elsevier Masson SAS.

U2 - 10.1016/j.ejmech.2011.02.063

DO - 10.1016/j.ejmech.2011.02.063

M3 - Article

SP - 2102

EP - 2108

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -