ABSTRACT
Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays.
Subject(s)
Acetates/toxicity , Amines , Cyclohexanecarboxylic Acids , Excitatory Amino Acid Antagonists/toxicity , Mitogens/toxicity , Pancreas/cytology , gamma-Aminobutyric Acid , Animals , Binding, Competitive/drug effects , Calcium/metabolism , Cell Division/drug effects , Cell Line , Gabapentin , Gene Expression Regulation, Neoplastic/drug effects , Genes, Immediate-Early , Organ Size/drug effects , Pancreas/drug effects , Pancreas/metabolism , Rats , Rats, Wistar , Receptors, Cholecystokinin/drug effects , Receptors, Cholecystokinin/metabolismABSTRACT
The major lipoxygenation product derived from linoleic acid, 13-(S)-hydroxyoctadecadienoic acid (13-HODE), has been shown to be involved in cell proliferation and differentiation in a number of systems. Rapid detection of picogram amounts of this bioactive lipid in biological samples, however, has been hindered due to lack of immunological reagents. In the current report, we have used a polyclonal antibody specific for 13-(S)-HODE to detect this bioactive lipid for the first time in human prostate adenocarcinoma specimens (PCa) and the prostate cancer cell lines LNCaP and PC-3 by enzyme immunoassay. In addition, we have verified-the quantitation of 13-HODE by chiral-phase HPLC and examined the levels of lipoxygenase expression by Western, Northern, and RT-PCR analysis. Immunohistochemically detectable 13-HODE was observed in human PCa, whereas adjacent normal tissue showed no immunoreactivity. The presence of 15-lipoxygenase was evident by Western and RT-PCR analysis in both LNCaP and PC-3 cells, while Northern blot analysis showed the presence of 15-lipoxygenase message in LNCaP cells but failed to detect any 15-lipoxygenase message in PC-3 cells. In contrast, quantitation of 13-HODE by enzyme immunoassay and chiral-phase HPLC showed significant levels of the compound in PC-3 cells but minimal enzymatically produced 13-HODE in LNCaP cells. These data provide a link between linoleic acid metabolism and the development or progression of prostate cancer.
