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Research Articles: Therapeutics

Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells

Division of Clinical Pharmacology, Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Giovanni Mario Pitari, Division of Clinical Pharmacology, Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, 1100 Walnut Street MOB 810, Philadelphia, PA 19107. Phone: 215-955-5647; Fax: 215-955-7006. E-mail: Giovanni.Pitari{at}jefferson.edu

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) Iß, 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 Iß, 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. [Mol Cancer Ther 2006;5(5):1190–6]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.A. Waldman is the Samuel M.V. Hamilton Professor. T. Li was enrolled in the NIH-supported institutional K30 Training Program in Human Investigation (K30 HL004522).

¹ Personal observation.

Received 10/10/05; revised 2/17/06; accepted 3/ 9/06.

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