The effects of a novel MEK inhibitor PD184161 on MEK-ERK signaling and growth in human liver cancer

Neoplasia : an International Journal for Oncology Research
Patrick J KleinJudith S Sebolt-Leopold

Abstract

The MEK-ERK growth signaling pathway is important in human hepatocellular carcinoma (HCC). To evaluate the targeting of this pathway in HCC, we characterized a novel, orally-active MEK inhibitor, PD184161, using human HCC cells (HepG2, Hep3B, PLC, and SKHep) and in vivo human tumor xenografts. PD184161 inhibited MEK activity (IC50 = 10-100 nM) in a time- and concentration-dependent manner more effectively than PD098059 or U0126. PD184161 inhibited cell proliferation and induced apoptosis at concentrations of > or = 1.0 microM in a time- and concentration-dependent manner. In vivo, tumor xenograft P-ERK levels were significantly reduced 3 to 12 hours after an oral dose of PD184161 (P < .05). Contrarily, tumor xenograft P-ERK levels following long-term (24 days) daily dosing of PD184161 were refractory to this signaling effect. PD184161 significantly suppressed tumor engraftment and initial growth (P < .0001); however, established tumors were not significantly affected. In conclusion, PD184161 has antitumor effects in HCC in vitro and in vivo that appear to correlate with suppression of MEK activity. These studies demonstrate that PD184161 is unable to suppress MEK activity in HCC xenografts in the long term. Thus, we speculate t...Continue Reading

References

Dec 1, 1995·Toxicology Letters·M SchwarzK W Bock
Jul 9, 1997·Biochemical and Biophysical Research Communications·C M SchmidtJ V Sitzmann
Nov 15, 1997·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·C M SchmidtJ V Sitzmann
Dec 16, 1997·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·I H McKillopJ V Sitzmann
Apr 16, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Y ItoM Hori
Jul 11, 1998·The Journal of Biological Chemistry·M F FavataJ M Trzaskos
Jan 27, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·I H McKillopJ V Sitzmann
Jan 27, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·I H McKillopJ V Sitzmann
Jun 4, 1999·Progress in Biophysics and Molecular Biology·M H Cobb
Jul 8, 1999·Nature Medicine·N S DuesberyG F Vande Woude
Jul 8, 1999·Nature Medicine·J S Sebolt-LeopoldA R Saltiel
Feb 2, 2000·European Journal of Gastroenterology & Hepatology·C M SchmidtJ V Sitzmann
Dec 22, 2000·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·K FukudaK Shimotohno
Mar 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·N S DuesberyG F Vande Woude
Jan 24, 2002·Trends in Pharmacological Sciences·Jessie M English, Melanie H Cobb
Mar 19, 2002·The Journal of Steroid Biochemistry and Molecular Biology·Richard J SantenWei Yue
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Oct 9, 2002·Current Pharmaceutical Design·Michelle Nottage, Lillian L Siu
Dec 31, 2002·Toxicology·Raffaella Romeo, Massimo Colombo
Feb 5, 2003·Onkologie·R A HilgerD Strumberg
Feb 21, 2003·International Journal of Cancer. Journal International Du Cancer·Keiran S M Smalley
Sep 27, 2003·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Takeya TsutsumiTatsuo Miyamura
Oct 7, 2003·Current Molecular Medicine·William B Coleman
Dec 12, 2003·Lancet·Josep M LlovetJordi Bruix
Mar 3, 2004·Journal of the American College of Surgeons·Chad A WiesenauerC Max Schmidt
Apr 13, 2004·Oncogene·Teiji Wada, Josef M Penninger
May 28, 2004·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Yeo Hyeon HwangYoung Min Park
Oct 16, 2004·Liver International : Official Journal of the International Association for the Study of the Liver·Yasunori TsuboiYutaka Aoyagi
Oct 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·John RinehartMark B Meyer
Apr 15, 2005·Journal of Gastroenterology·Josep M Llovet
Apr 16, 2005·Clinics in Liver Disease·F Xavier BoschMireia Díaz
Jun 21, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sabine StahlMichael Schwarz
Jul 13, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Patricia M LorussoMark B Meyer

❮ Previous
Next ❯

Citations

Feb 11, 2014·Bioorganic & Medicinal Chemistry·Wiktor SzymanskiRyszard Ostaszewski
Apr 27, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bert H O'NeilDaniel M Sullivan
Apr 29, 2009·World Journal of Gastroenterology : WJG·Wei CuiKe-Qin Hu
Feb 1, 2014·Breast Cancer Research : BCR·Manish TandonJitesh Pratap
Dec 3, 2010·Journal of Cancer Research and Clinical Oncology·Roland KaufmannUtz Settmacher
May 13, 2008·The Journal of Surgical Research·Jennifer ChoiC Max Schmidt
Oct 31, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Bing-Sheng SunLun-Xiu Qin
Oct 2, 2008·Journal of Thrombosis and Haemostasis : JTH·F AdamM Bryckaert
Aug 14, 2012·The Laryngoscope·Brian A NeffHirohito Kita
Jan 30, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Matthew HennigC Max Schmidt
Oct 10, 2009·International Journal of Cancer. Journal International Du Cancer·Luc GailhousteGeorges Baffet
May 8, 2007·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Giampaolo TortoraMichele Milella
May 30, 2006·Biochemical and Biophysical Research Communications·Shigeru KandaYasuyoshi Miyata
Sep 21, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Zheng DangXianghui Wang
Apr 3, 2015·European Journal of Clinical Investigation·Bénédicte Delire, Peter Stärkel
Aug 19, 2015·The Journal of Clinical Investigation·Nina BögershausenBernd Wollnik
Nov 8, 2012·International Journal of Hepatology·Jean-Philippe GuéganGeorges Baffet
Dec 26, 2006·Biochimica Et Biophysica Acta·Jean-Claude ChambardPhilippe Lenormand
Sep 29, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ying Cheng, Hongqi Tian
Aug 18, 2017·Molecular Pharmacology·Maroua JalouliDarren E Richard
May 11, 2010·Sexually Transmitted Diseases·Toan H HaTiejian Feng
Feb 15, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kathryn TrandemStanley Perlman
Jun 24, 2020·Journal of Thrombosis and Haemostasis : JTH·Pravin Patel, Ulhas P Naik
Jan 16, 2016·Molecular Biology Reports·Amir MehdizadehMortaza Jabbarpour-Bonyadi
May 6, 2017·Clinical and Translational Medicine·Osamu Tetsu, Frank McCormick
Apr 4, 2012·Oncotarget·Melchiorre CervelloGiuseppe Montalto
Jan 20, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aidan G GilmartinSylvie G Laquerre
Mar 29, 2021·European Journal of Medicinal Chemistry·Chao WangPing Xu
Nov 9, 2021·Frontiers in Cellular and Infection Microbiology·Sheryl Erica Fernandes, Deepak Kumar Saini

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