N-methylformamide and 9-hydroxystearic acid: two anti-proliferative and differentiating agents with different modes of action in colon cancer cells.
N-methylformamide (NMF) is an anti-proliferative, differentiating agent studied in several cell lines as well as in preclinical and clinical trials, whose mechanisms of action are still unclear. 9-Hydroxystearic acid (9-HSA) is an endogenous product of lipid peroxidation recently identified as a new histone deacetylase 1 inhibitor. Both agents show the same anti-proliferative effects by arresting colon cancer cell growth in G0/G1. We addressed two questions. (i) Do they act by regulating G0/G1 checkpoint proteins? (ii) Does 9-HSA have differentiating effects comparable to those of NMF? The effects of NMF and 9-HSA on growth, differentiation and invasiveness of HT29, a colon cancer cell line, have been compared by using immunoprecipitation analysis, confocal microscopy, enzyme assays and invasiveness tests. The results show that the G1 arrest caused by NMF is a cell cycle exit due to p27 induction, whereas 9-HSA has no effect on the induction of this inhibitor. Evidence is presented that the arrest in early G0/G1 induced by 9-HSA is associated with the conversion of HT29 characteristics to those of a more benign phenotype, whereas the arrest in the late G1 in response to NMF is not followed by a decrease in tumorigenicity. The failure of NMF in cancer therapy indicates that both anti-proliferative and differentiating characteristics are required for an anti-tumoral agent to be effective.
Pagnotta
Eleonora
E
Department of Biochemistry G. Moruzzi, Bologna, Italy. eleonora.pagnotta3@unibo.it
Calonghi
Natalia
N
Boga
Carla
C
Masotti
Lanfranco
L
D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects; D005559:Formamides / Q000494:pharmacology*; D006801:Humans; D018613:Microscopy, Confocal; D013229:Stearic Acids / Q000494:pharmacology*
D005559:Formamides; D013229:Stearic Acids; C070375:9-hydroxystearic acid; C002950:methylformamide