Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 3, pp 487–495 | Cite as

KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma

  • Yun Zheng
  • Sigal GeryEmail author
  • Haibo Sun
  • Sharon Shacham
  • Michael Kauffman
  • H. Phillip Koeffler
Original Article



Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).


In silico, meta-analysis showed that XPO1 is overexpressed in HCC. Six HCC cell lines were treated with KPT-330, and cell proliferation and expression of cell growth regulators were examined by cell proliferation assays and Western blot analysis, respectively. The in vivo anti-cancer activity of KPT-330 was examined in a HCC xenograft murine model.


KPT-330 reduced the viability of HCC cell lines in vitro and this anti-proliferative effect was associated with cell cycle arrest and induction of apoptosis. The expression of the pro-apoptotic protein PUMA was markedly up-regulated by KPT-330. In addition, SINE treatment increased the expression of the tumor suppressor proteins p53 and p27, while it reduced the expression of HCC promoting proteins, c-Myc and c-Met. XPO1 levels itself were also down-regulated following KPT-330 treatment. Finally, a HCC xenograft murine model showed that treatment of mice with oral KPT-330 significantly inhibited tumor growth with little evidence of toxicity.


Our results suggest that SINE compounds, such as KPT-330, are promising novel drugs for the targeted therapy of HCC.


Hepatocellular carcinoma XPO1 inhibitor Apoptosis Xenograft 



H. P. K. is the holder of the Mark Goodson endowed Chair in Oncology Research and is a member of the Jonsson Cancer Center and the Molecular Biology Institute, UCLA. In addition, we thank Blanche and Steven Koegler for their generous support. This work was supported by NIH Grants (2R01 CA026038-35, 5R01AI65604-6), SWLF, the Tom Collier Memorial Regatta Foundation, East Meets West Cedars-Sinai Fund, as well as, A*STAR of Singapore.

Conflict of interest

S.S. and M.K. are employees of Karyopharm Therapeutics, a clinical stage biopharmaceutical company that develops selective inhibitors of nuclear export-targeted therapeutics. The remaining authors declare no competing financial interests.

Supplementary material

280_2014_2495_MOESM1_ESM.pptx (2 mb)
Supplementary material 1 (PPTX 2,058 kb)
280_2014_2495_MOESM2_ESM.docx (20 kb)
Supplementary material 2 (DOCX 20 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yun Zheng
    • 1
    • 2
  • Sigal Gery
    • 2
    Email author
  • Haibo Sun
    • 2
  • Sharon Shacham
    • 3
  • Michael Kauffman
    • 3
  • H. Phillip Koeffler
    • 2
    • 4
  1. 1.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina
  2. 2.Hematology/Oncology, Cedars-Sinai Medical CenterUCLA School of MedicineLos AngelesUSA
  3. 3.Karyopharm TherapeuticsNatickUSA
  4. 4.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore

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