Pentoxifylline-induced modulation of melanoma cell growth, adhesion and lymphokine activated killer cell-mediated lysis.
Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively increases overall cAMP levels within the cell. This study analyses the ability of PX to alter growth, adhesion and lymphokine activated killer (LAK) cell-mediated lysis of the C8161 and Hs294T human melanoma cell lines, and investigates the role of intercellular adhesion molecule-1 (ICAM-1) in the tumour/LAK cell interaction. We have demonstrated that 4 days' pretreatment with PX (100-250 microg/ml) significantly reduces cell numbers in a dose- and time-dependent manner, with cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the Hs294T cell line with 250 microg/ml PX. Adherence of both cell lines to a range of extracellular matrix components is not affected by PX, with the exception of the C8161 cells, where 4 days' pretreatment with 250 microg/ml PX causes a 24.2% reduction in adherence to fibronectin. Four days' pretreatment of the tumour cells with 250 microg/ml PX leads to increased lysis of the C8161 cells and decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10 microg/ml) to the C8161 cells at an effector:tumour cell ratio of 40:1 causes a 2.3-fold reduction in lysis of both control and PX-treated cells. Addition of blocking ICAM-1 antibody (5 microg/ml) to Hs294T cells reduces lysis of control cells 1.8-fold. In PX-treated Hs294T cells, 10 microg/ml of blocking ICAM-1 antibody significantly reduces lysis 1.5-fold. The more aggressive C8161 cells produce 5-fold greater levels of soluble ICAM-1 (sICAM-1) than the poorly metastatic Hs294T cells. PX (10-250 microg/ml) causes a dose-dependent increase in sICAM-1 expression in both cell lines, with maximum increases of 4.7-fold and 4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days' pretreatment with 250 microg/ml PX. Collectively, these data demonstrate the ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis and also support a role for the involvement of ICAM-1 in the tumour/LAK cell interaction.
Alexander
C L
CL
Department of Dermatology, University of Glasgow, Scotland, UK. ca9p@udcf.gla.ac.uk
Edward
M
M
MacKie
R M
RM
D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D010726:Phosphodiesterase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D010431:Pentoxifylline