Acetylsalicylic acid and salicylic acid decrease tumor cell viability and glucose metabolism modulating 6-phosphofructo-1-kinase structure and activity.
The common observation that cancer cells present higher glycolytic rates when compared to control cells leads to the proposal of glycolysis as a potential target for the development of anti-tumoral agents. Anti-inflammatory drugs, such as acetylsalicylic acid (ASA) and salicylic acid (SA), present anti-tumoral properties, inducing apoptosis and altering tumor glucose utilization. The present work aims at evaluating whether ASA could directly decrease cell glycolysis through inhibition of the major regulatory enzyme within this pathway, 6-phosphofructo-1-kinase (PFK). We show that ASA and SA inhibit purified PFK in a dose-dependent manner, and that this inhibition occurs due to the modulation of the enzyme quaternary structure. ASA and SA promote the dissociation of the enzyme active tetramers into quite inactive dimers, a common regulatory mechanism of this enzyme. The inhibitory effects of ASA and SA on PFK are fully reversible and can be prevented or reverted by the binding of the enzyme to the actin filaments. Both drugs are also able to decrease glucose consumption by human breast cancer cell line MCF-7, as well as its viability, which decrease parallelly to the inhibition of PFK on these cells. In the end, we demonstrate the ability of ASA and SA to directly modulate an important regulatory intracellular enzyme, and propose that this is one of their mechanisms promoting anti-tumoral effects.
Laboratório de Oncobiologia Molecular (LabOMol), Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil.
Guilherme A
GA
Spitz
Cristiane M
CM
Furtado
Mauro
M
Sola-Penna
Patricia
P
Zancan
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D020156:Salicylic Acid / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010732:Phosphofructokinase-1; D005947:Glucose; D020156:Salicylic Acid; D001241:Aspirin