title: Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells.
abstract: The nonsteroidal anti-inflammatory drug sulindac is metabolized to sulindac sulfone (exisulind), an antineoplastic agent that inhibits growth and induces apoptosis in solid tumors. In colon cancer cells, the antineoplastic effects of exisulind have been attributed, in part, to induction of cyclic guanosine 3',5'-monophosphate (cGMP) signaling through inhibition of cGMP-specific phosphodiesterases, which elevates intracellular cGMP, and novel expression of cGMP-dependent protein kinase (PKG) Ibeta, the presumed downstream effector mediating apoptosis. Here, inhibition of proliferation and induction of cell death by exisulind was dissociated from cGMP signaling in human colon cancer cells. Accumulation of intracellular cGMP produced by an exogenous cell-permeant analogue of cGMP or a potent agonist of guanylyl cyclase C yielded cytostasis without cell death. Surprisingly, the antiproliferative effects of induced cGMP accumulation were paradoxically less than additive, rather than synergistic, when combined with exisulind. Further, although exisulind induced expression of PKG Ibeta, it did not elevate intracellular cGMP and its efficacy was not altered by inhibition or activation of PKG I. Rather, PKG I induced by exisulind may mediate desensitization of cytostasis induced by cGMP. Thus, cytotoxic effects of exisulind are independent of cGMP signaling in human colon cancer cells. Moreover, combination therapies, including exisulind and agents that induce cGMP signaling, may require careful evaluation in patients with colon cancer.
authors.affiliation: Division of Clinical Pharmacology, Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, 1100 Walnut Street MOB 810, Philadelphia, PA 19107, USA. Giovanni.Pitari@jefferson.edu
authors.forename: Giovanni Mario
authors.initials: GM
authors.lastname: Pitari
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Ronnie I
authors.initials: RI
authors.lastname: Baksh
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide; D015398:Signal Transduction / Q000187:drug effects; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D018000:Receptors, Peptide; D013467:Sulindac; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP; C025463:sulindac sulfone