Modulation of tumor cell proliferation and apoptosis by polyamine depletion in cells of head and neck squamous cell carcinomas.
These studies were carried out to examine the capacity of alpha-difluoromethylornithine (DFMO) to modulate cell proliferation and apoptosis in cells of squamous cell carcinomas (SCCs) of the head and neck. Exposure of cells to DFMO (5 mM for 48 h) depleted intracellular putrescine and spermidine levels (greater than 5-fold) and inhibited proliferation of the cells without manifestation of cytotoxicity as measured by a clonogenic assay. Exposure of the cells to DFMO did not influence the survival response after exposure to single-dose radiation between 0 and 10 Gy. Treatment of polyamine-depleted cells with 200 nM staurosporine amplified apoptosis 65% (1.65-fold) over that in controls, as determined by flow cytometry. The increased apoptosis after DFMO treatment was effectively inhibited by the addition of 1 mM putrescine or spermidine. Cleavage of poly(ADP-ribose) polymerase (PARP) illustrated that the staurosporine treatment induced apoptosis in the cells within 6 h. Analysis of PARP cleavage indicated that treatment with DFMO accelerated the kinetics of progression of apoptosis but did not influence the sensitivity of cells to 10 nM-1 microM staurosporine. These data suggest an involvement of endogenous polyamines in modulation of proliferation kinetics and apoptosis in human SCCs and suggest opportunities to explore new therapeutic strategies in head and neck cancer patients to be treated with radiation therapy.
Bock
J M
JM
Department of Human Oncology, University of Wisconsin School of Medicine, Madison, Wisconsin 53792-0600, USA.
Pickart
M A
MA
Pink
J J
JJ
Harari
P M
PM
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D011073:Polyamines; D011065:Poly(ADP-ribose) Polymerases; D019311:Staurosporine; D000518:Eflornithine