Ethyl pyruvate administration inhibits  hepatic tumor growth.
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.
Liang
Xiaoyan
X
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Chavez
Antonio Romo de Vivar
AR
Schapiro
Nicole E
NE
Loughran
Patricia
P
Thorne
Stephen H
SH
Amoscato
Andrew A
AA
Zeh
Herbert J
HJ
Beer-Stolz
Donna
D
Lotze
Michael T
MT
de Vera
Michael E
ME
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D017930:Genes, Reporter; D005822:Genetic Vectors; D024243:HMGB1 Protein / Q000378:metabolism; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D049410:Luciferases, Renilla / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011773:Pyruvates / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein; D015850:Interleukin-6; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011773:Pyruvates; C046522:ethyl pyruvate; D049410:Luciferases, Renilla; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases