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2014 ; 74
(3
): 487-95
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KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity
in hepatocellular carcinoma
#MMPMID25030088
Zheng Y
; Gery S
; Sun H
; Shacham S
; Kauffman M
; Koeffler HP
Cancer Chemother Pharmacol
2014[Sep]; 74
(3
): 487-95
PMID25030088
show ga
PURPOSE: 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). METHODS: 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. RESULTS: 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.
CONCLUSION: Our results suggest that SINE compounds, such as KPT-330, are
promising novel drugs for the targeted therapy of HCC.
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