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Originally published online as doi:10.1189/jlb.0908578 on July 9, 2009

Published online before print July 9, 2009
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(Journal of Leukocyte Biology. 2009;86:599-607.)
© 2009 Society for Leukocyte Biology

Ethyl pyruvate administration inhibits hepatic tumor growth

Xiaoyan Liang*,{dagger}, Antonio Romo de Vivar Chavez*,{dagger}, Nicole E. Schapiro{dagger}, Patricia Loughran{dagger}, Stephen H. Thorne{dagger}, Andrew A. Amoscato{dagger}, Herbert J. Zeh{dagger}, Donna Beer-Stolz{ddagger}, Michael T. Lotze{dagger} and Michael E. de Vera*,{dagger},1

* Thomas E. Starzl Transplantation Institute,
{dagger} University of Pittsburgh Cancer Institute, and
{ddagger} Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

1. Correspondence: Starzl Transplantation Institute, UPMC Montefiore, 7 South, 3459 Fifth Ave., Pittsburgh, PA 15213, USA. E-mail: deverame{at}upmc.edu

ABSTRACT

EP is a potent inhibitor of HMGB1 release that has significant anti-inflammatory activities and exerts a protective effect in animal models of inflammation. As inflammation is linked to cancer growth, we hypothesized that EP would have anti-tumor activity and explored its effects in a liver tumor model. Mice injected intraportally with MC38 colorectal cancer cells led to the growth of visible hepatic tumors within 2 weeks. Pretreatment with EP 30 min prior to infusion of tumor cells and continuing daily for 9 days inhibited tumor growth significantly in a dose-dependent manner, with 80 mg/kg EP achieving >70% reduction in the number of tumor nodules when compared with untreated animals. Delayed treatment with EP also suppressed tumor growth significantly, although to a lesser extent. Tumors had early, marked leukocytic infiltrates, and EP administration decreased innate (NK cells, monocytes) and adaptive (T and B cell lymphocytic) immune cell infiltrates acutely and significantly in the liver. Serum IL-6 and HMGB1 levels, which were elevated following tumor injection, were decreased significantly in EP-treated animals. Tumors showed an increase in apoptosis in EP-treated mice, and tumor cells treated in vitro with EP had marked increases in LC3-II and cleaved PARP, consistent with enhanced autophagic flux and apoptosis. Thus, EP inhibition of tumor growth in the liver was mediated by tumor (induction of apoptosis) and host (decreased inflammation) effects. EP administration may have a therapeutic role in the treatment of cancer in conjunction with other therapeutic agents.

Key Words: metabolism • cancer models • liver metastases • colorectal cancer • inflammation • HMGB1 • apoptosis • autophagy