Carcinogenesis Advance Access published online on February 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh122
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970
Received 26 October 2003
; revised 19 January 2004
; accepted 10 February 2004
Retinoids may be useful agents for the treatment of pancreatic cancer. However, RAR-selective retinoids produce unwanted side effects. In contrast, RXR-selective retinoids produce fewer side effects; however, it was not known whether RXR-selective retinoids can reduce pancreatic tumor cell proliferation. In the present study, the novel RXR-selective retinoid, AGN194204, was compared with that of other retinoids for ability to suppress pancreatic cancer cell proliferation. We treated various pancreatic cancer cell lines with various receptor-selective ligands and cytotoxic agents and monitored the effects on cell proliferation, markers of apoptosis and cell cycle markers. Our results indicate that AGN194204, at concentrations greater than 10 nM, inhibits proliferation of MIA PaCa-2 and BxPC-3 cells but not the proliferation of AsPC-1 cells. Moreover, in BxPC-3 and MIA PaCa-2 cells, AGN194204 was 10-100 times more effective than RAR-selective retinoids. AGN194204-dependent suppression of MIA PaCa-2 cell proliferation is associated with reduced cyclin E and cyclin-dependent kinase 6 (cdk6) level, but cyclin D1, cdk2 and cdk4 content is not altered. In addition, p27 level increases two-fold. The RXR-selective antagonist, AGN195393, reverses the AGN194204-dependent growth inhibition and the decline in cyclin E and cdk6 levels. In contrast, these changes are not reversed by treatment with the RAR antagonist, AGN193109. AGN194204 did not appear to alter cell apoptosis as measured by change in cleavage of procaspase-3, -8 or -9. We also examined the effects AGN194204 cotreatment with cytotoxic agents. Treatment of MIA PaCa-2 cells with AGN194204 + cisplatin, gemcitabine, 5-flurouracil, interferon-
Pancreatic cancer, retinoids, cytotoxic agents, interferon-Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid
2 Department of Chemistry, Allergan, Inc.
3 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970; Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970; Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970; Department of Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970
or interferon-
resulted in an additive but not synergistic reduction in MIA PaCa-2 cell number. These results indicate that AGN194204, an RXR-selective retinoid, is a more effective inhibitor of pancreatic cell proliferation than the RAR-selective retinoids, and further indicate that AGN194204 produces an additive reduction in cell number when given with other agents. Our results suggest that RXR-selective ligands, which are less toxic than RAR-selective ligands, may be suitable agents for the treatment of pancreatic cancer., interferon-
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