Antitumoral activity of a trichloromethyl pyrimidine analogue: molecular cross-talk between intrinsic and extrinsic apoptosis.
Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.
Departamento de Ciências Farmacêuticas, Programa de Pós-graduação em Farmácia, Universidade Federal de Santa Catarina , 88040-900 Florianópolis SC, Brazil.
Evelyn
E
Winter
Carine
C
Dal Pizzol
Fabíola B
FB
Filippin-Monteiro
Patrícia
P
Brondani
Andreia M P W
AM
Silva
Adny H
AH
Silva
Helio G
HG
Bonacorso
Marcos A P
MA
Martins
Nilo
N
Zanatta
Tânia B
TB
Creczynski-Pasa
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C000597458:1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethylpyrimidin-2(1H)-one; D000970:Antineoplastic Agents; D011744:Pyrimidinones