Abstract
Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells. In the present study amylase release has been used to assess the mechanisms by which the photodynamic drugs tetra- and disulphonated aluminium phthalocyanine (A1PcS4, A1PcS2) act on pancreatic cells via energy and calcium-dependent activation and transduction pathways. The photodynamic release of amylase was found to be energy dependent and inhibited by the chelation of free cytoplasmic calcium but not by the removal of extracellular calcium. In contrast to their effects on normal acinar cells, the photodynamic action of A1PcS4 and A1PcS2 was to inhibit amylase secretion from pancreatoma AR4-2J cells. Removal of extracellular calcium reversed this inhibitory effect on AR4-2J cells and produced a significant increase in amylase release, but chelation of free cytoplasmic calcium did not affect the inhibitory photodynamic action of the phthalocyanines on amylase release from the tumour cells. Overall, these results demonstrate further important distinctions between the photodynamic action of sulphonated aluminium phthalocyanines on normal versus tumour exocrine cells of the pancreas and indicate that calcium plays an important role in photodynamic drug action, since these agents affected intracellular calcium mobilisation at some distal point in the membrane signal transduction pathway for regulated secretion. Furthermore, the photodynamic inhibition of constitutive secretion in tumour cells may involve a calcium-dependent membrane target site or modulation of membrane calcium channels by activation of protein kinase C.
Highlights
S_n.mary Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells
The objective of the present study was to examine the role of calcium and the participation of signal transduction mechanisms in the release of amylase from normal pancreatic acinar cells and from tumour cells of the AR4-2J cell line when stimulated with light-activated phthalocyanines
We have taken advantage of the availability of the tetra- and disulphonated derivatives of aluminium phthalocyanine, which differ in their lipophilic properties (Berg et al.. 1989). in order to compare the photodynamic potency of the two compounds on pancreatic cells
Summary
Pancreatic acini from male Sprague - Dawley rats (250-450 g). were freshly isolated by collagenase digestion as. AR4-2J cells, a cell lne derived from an a ine uced carcinoma of the pancreas in the rat (Longnecker et al, 1979) were grown in tissue culture dishes (90mm diameter) in RPMI nmdium (Gibco) supplemeted with penclin-stptomycin (100 IU ml-'), L-glutamine (2 mM) and fetal calf serum (final concentration 10%) at 37C in a 95% air/5% carbon dioxide atmosphere. Cells were harvested by incubation with EDTA solution (0.025% EDTA) for 5 min and with trypsin solution (0.25% trypsin, in phosphate buffer containing 0.025% EDTA, and 0.8% glucose). The cells from each dish were harvested and divided between five further culture dishes. The cells were harvested in a simplified buffer rm mM, sodium chloride 118, potassium chloride 4.7, magnesum chloride 1.16, calcium chloride 2.0, sodium phosphate 1.16 ghloe 14, HEPES 10; the pH was adjusted to 7.3 with. Up to five culture dishes of near-confluent cells were used for each experiment
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