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PI‐25
Author(s) -
Pitari G. M.,
Baksh R. I.,
Harris D. M.,
Li P.,
Kazerounian S.,
Waldman S. A.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.046
Subject(s) - cytostasis , cyclic nucleotide , chemistry , cancer research , allosteric regulation , tachyphylaxis , microbiology and biotechnology , pharmacology , biology , biochemistry , nucleotide , receptor , cytotoxicity , in vitro , gene
BACKGROUND Bacterial diarrheagenic heat‐stable enterotoxins (STs) induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Although the molecular pathway involving cGMP‐dependent influx of Ca 2+ through cyclic nucleotide‐gated (CNG) channels has been elucidated, the long‐term kinetics of the antineoplastic effects of these toxins remain undefined. METHODS GCC signaling inducing cytostasis was examined in human colon carcinoma T84 cells employing radioimmunoassay for cGMP, unidirectional 45 Ca 2+ current, 3 H‐thymidine incorporation into the DNA and flow cytometry. RESULTS Prolonged stimulation of GCC produced resistance in tumor cells to ST‐induced cytostasis. Resistance reflected rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis was mediated by cGMP‐dependent protein kinase, which reduced the influx of Ca 2+ through CNG channels. In contrast, bradyphylaxis was mediated by cGMP‐dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude of ST‐dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachy‐ and bradyphylaxis restored cancer cell cytostasis induced by ST. CONCLUSIONS Regimens that incorporate cytostatic bacterial enterotoxins and inhibitors of cGMP‐mediated desensitization offer a previously unrecognized therapeutic paradigm for treatment and prevention of colorectal cancer. Clinical Pharmacology & Therapeutics (2005) 79 , P13–P13; doi: 10.1016/j.clpt.2005.12.046