Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate.
Efforts to improve cancer care in the developing world will benefit from the identification of simple, inexpensive, and broadly applicable medical modalities based on emergent innovations in treatment, such as targeting mechanisms of tumoral immune tolerance. In this report, we offer preclinical evidence that the low-cost, anti-inflammatory agent ethyl pyruvate elicits a potent immune-based antitumor response through inhibition of indoleamine 2,3-dioxygenase (IDO), a key tolerogenic enzyme for many human tumors. Consistent with its reported ability to interfere with NF-kappaB function, ethyl pyruvate blocks IDO induction both in vitro and in vivo. Antitumor activity was achieved in mice with a noncytotoxic dosing regimen of ethyl pyruvate shown previously to protect against lethality from sepsis. Similar outcomes were obtained with the functional ethyl pyruvate analogue 2-acetamidoacrylate. Ethyl pyruvate was ineffective at suppressing tumor outgrowth in both athymic and Ido1-deficient mice, providing in vivo corroboration of the importance of T-cell-dependent immunity and IDO targeting for ethyl pyruvate to achieve antitumor efficacy. Although ethyl pyruvate has undergone early-phase clinical testing, this was done without consideration of its possible applicability to cancer. Our findings that IDO is effectively blocked by ethyl pyruvate treatment deepen emerging links between IDO and inflammatory processes. Further, these findings rationalize oncologic applications for this agent by providing a compelling basis to reposition ethyl pyruvate as a low-cost immunochemotherapy for clinical evaluation in cancer patients.
Muller
Alexander J
AJ
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
DuHadaway
James B
JB
Jaller
Daniel
D
Curtis
Peter
P
Metz
Richard
R
Prendergast
George C
GC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011773:Pyruvates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D020298:U937 Cells
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011773:Pyruvates; D012333:RNA, Messenger; C046522:ethyl pyruvate