Targeting mitogen-activated protein Kinase Kinase with the inhibitor pd0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems

Matthew Hennig, Michele Yip-Schneider, Sabrina Wentz, Huangbing Wu, S. K. Hekmatyar, Patrick Klein, Navin Bansal, C. Schmidt

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Abstract

Hepatocellular carcinoma (HCC) is a common cause of death from solid organ malignancy worldwide. Extracellular signal-regulated/mitogen-activated protein kinase kinase (MEK) signaling is a critical growth regulatory pathway in HCC. Targeting MEK with a novel small molecule inhibitor, PD0325901, may inhibit HCC tumorigenesis. PD0325901 (0.01-100 nM) inhibited growth and MEK activity in vitro in immortalized murine transforming growth factor alpha (TGF-α) transgenic hepatocyte (TAMH) cells, derived from the livers of TGF-α transgenic mice. Treatment of athymic mice bearing TAMH flank tumors with vehicle or PD0325901 (20 mg/kg) revealed a significant reduction of MEK activity ex vivo 24 hours after a single PD0325901 dose. The growth rate of TAMH flank tumors over 16 days was reduced threefold in the treatment arm (1113 ± 269% versus 3077 ± 483%, P < 0.01). PD0325901 exhibited similar inhibitory effects in HepG2 and Hep3B human HCC cells in vitro and in Hep3B flank tumors in vivo. To confirm this in a developmental model, MT-42 (CD-1) TGF-αmice were treated with vehicle or PD0325901 (20 mg/kg) for 5 weeks. Gross HCC was detected in 47% and 13.3% of the control and treatment mice, respectively. Tumor growth suppression by PD0325901 relative to vehicle was also shown by magnetic resonance imaging. These studies provide compelling preclinical evidence that targetingMEKin human clinical trials may be promising for the treatment of HCC.

Original languageEnglish
Pages (from-to)1218-1225
Number of pages8
JournalHepatology
Volume51
Issue number4
DOIs
StatePublished - Apr 2010

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Mitogen-Activated Protein Kinase Kinases
Hepatocellular Carcinoma
Transforming Growth Factor alpha
Growth
Neoplasms
In Vitro Techniques
PD 0325901
Nude Mice
Transgenic Mice
Cause of Death
Hepatocytes
Carcinogenesis
Magnetic Resonance Imaging
Clinical Trials

ASJC Scopus subject areas

  • Hepatology

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Targeting mitogen-activated protein Kinase Kinase with the inhibitor pd0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. / Hennig, Matthew; Yip-Schneider, Michele; Wentz, Sabrina; Wu, Huangbing; Hekmatyar, S. K.; Klein, Patrick; Bansal, Navin; Schmidt, C.

In: Hepatology, Vol. 51, No. 4, 04.2010, p. 1218-1225.

Research output: Contribution to journalArticle

Hennig, Matthew ; Yip-Schneider, Michele ; Wentz, Sabrina ; Wu, Huangbing ; Hekmatyar, S. K. ; Klein, Patrick ; Bansal, Navin ; Schmidt, C. / Targeting mitogen-activated protein Kinase Kinase with the inhibitor pd0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. In: Hepatology. 2010 ; Vol. 51, No. 4. pp. 1218-1225.
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