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Dopamine and Tumorigenesis in Reproductive Tissues
Published in Nira Ben-Jonathan, Dopamine, 2020
Although there is only limited documentation on a direct effect of DAR activation on prostate cancer, similar to breast cancer, DA may activate the NO/cGMP/PKG pathway in prostate cancer. The involvement of this pathway in chemosensitivity of DU145 and PC-3 prostate cancer cells was confirmed by showing that inhibitors of sGC and PKG increased drug resistance [94]. Moreover, direct activation of PKG with 8-Br-cGMP attenuated the acquisition of hypoxia-induced resistance to doxorubicin in these cells. Another study found that exisulind, which acts by activating PKG, had antineoplastic activity in rodent models of colon, prostate, bladder, mammary and lung cancer [95]. The authors pointed out that in a randomized, placebo-controlled trial of prostate cancer patients, exisulind inhibited the rise of PSA in men with PSA progression after radical prostatectomy. Both preclinical and early clinical data suggested that exisulind and similar drugs in this class could be useful in treating various cancers both as monotherapy and in combination with chemotherapy and other targeted agents.
An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer
Published in Expert Review of Clinical Pharmacology, 2020
Jeffrey A. Rappaport, Scott A. Waldman
Initial efforts to test PDE inhibition for chemoprevention in humans focused on the pan-PDE inhibitor, exisulind, in patients with FAP and sporadic adenomas [83–85]. Although exisulind treatment resulted in polyp regression, these trials were largely abandoned as a result of significant hepatotoxicity. Another agent, the non-aspirin NSAID, sulindac, has been shown to reduce polyp formation in patients with FAP, although its use is restricted by gastrointestinal toxicity arising from cyclooxygenase(COX)-inhibition [86,87]. The chemopreventative effects of sulindac may be mediated by a COX-independent mechanism involving PDE inhibition and activation of cGMP signaling [65,88]. Sulindac derivatives retaining PDE-inhibitory activity and lacking COX-inhibitory activity have been proposed for chemoprevention without gastrointestinal toxicity [89]. Recent efforts have focused on inhibition of PDE5 with sildenafil (Viagra), which benefits from decades of use and a well-documented safety profile. In APCmin/+ mice, sildenafil administered in drinking water reduced the number of polyps by 50% [78]. Similar results were observed in an inflammatory model of tumorigenesis, where sildenafil administration opposed intestinal inflammation and polyp multiplicity [90]. Interestingly, the anti-neoplastic effect of sildenafil was only observed when administered prior to the neoplastic insult (azoxymethane), consistent with reported geno-protective roles of cGMP.
Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
Ariana A. Entezari, Adam E. Snook, Scott A. Waldman
Exisulind, a derivative of the NSAID sulindac, induces apoptosis in SW480 cells through PKG-mediated inhibition of oncogenic β-catenin activity. Exisulind inhibits PDE5 and PDE2, elevating intracellular cGMP levels and thereby activating PKG. PKG phosphorylates β-catenin and mediates apoptosis in these cells [79]. Furthermore, exisulind reduced tumor incidence and multiplicity in a rat model of carcinogen (azoxymethane)-induced tumorigenesis [80]. Clinically, exisulind prevented colorectal polyp formation in FAP patients over 24 months [81]. Exisulind treatment produced tumor cell apoptosis and polyp regression, but hepatic toxicity prevented FDA approval [81].