A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity.

Cancer Prevention Research
Jason D WhittGary A Piazza

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin lev...Continue Reading

References

May 15, 1976·International Journal of Cancer. Journal International Du Cancer·C Sundström, K Nilsson
Feb 1, 1993·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·T M Lincoln, T L Cornwell
May 6, 1993·The New England Journal of Medicine·F M GiardielloG J Offerhaus
Mar 10, 2000·Advances in Experimental Medicine and Biology·G D StonerR U van Stolk
Aug 31, 2001·JAMA : the Journal of the American Medical Association·D MukherjeeE J Topol
Mar 16, 2002·Neoplasia : an International Journal for Oncology Research·Daniel H HwangAndrew J Dannenberg
Jul 30, 2003·Lancet·Paul J KimDario C Altieri
Sep 16, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lajos PusztaiGabriel N Hortobagyi
Oct 13, 2004·Mutation Research·Margie L ClapperWen-Chi L Chang
Apr 5, 2005·The Journal of Pharmacology and Experimental Therapeutics·Basil Rigas, Khosrow Kashfi
Jul 21, 2005·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Jan J KoornstraJan H Kleibeuker
Nov 26, 2009·Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract·Michael David JohnsonR Matthew Walsh
Jul 9, 2010·CA: a Cancer Journal for Clinicians·Ahmedin JemalElizabeth Ward
Feb 12, 2011·Expert Review of Gastroenterology & Hepatology·Joseph C Anderson
May 3, 2011·The American Journal of Medicine·Edward S HuangAndrew T Chan

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Citations

Sep 1, 2014·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Tarek Aboul-FadlMohammed K Abdel-Hamid
Jul 28, 2015·Current Pharmacology Reports·Ruixia MaYaguang Xi
Aug 31, 2014·Pharmacology & Therapeutics·Phuong N LeAntonio Jimeno
Mar 6, 2013·Current Colorectal Cancer Reports·Heather N Tinsley, Gary A Piazza
May 13, 2014·Asian Pacific Journal of Cancer Prevention : APJCP·Ahmet AltunTijen Temiz Kaya
Jan 16, 2015·The Journal of Pharmacology and Experimental Therapeutics·Basil Rigas, George J Tsioulias
Feb 11, 2020·Cancer Biology & Therapy·Erik S BlomainScott A Waldman
Dec 13, 2017·Oncotarget·Ines BaroneStefania Catalano
Dec 22, 2015·Current Pharmacology Reports·George J TsiouliasBasil Rigas
Apr 20, 2018·Future Medicinal Chemistry·Bini MathewRobert C Reynolds
Sep 19, 2020·Expert Review of Clinical Pharmacology·Jeffrey A Rappaport, Scott A Waldman
Feb 28, 2020·World Journal of Gastrointestinal Oncology·Wen-Qi CuiLi-Xuan Sang
Apr 4, 2014·Cancer Prevention Research·James R Goodman, Douglas Grossman
Jan 6, 2018·Cancer Prevention Research·Sarah K SharmanDarren D Browning
Jun 11, 2017·Cancer Prevention Research·Gary A Piazza
Dec 7, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Evrim GurpinarGary A Piazza
Jan 21, 2021·Biomarkers in Medicine·John C FlickingerScott A Waldman

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