T-3256336, a novel and orally available small molecule IAP antagonist, induced tumor cell death via induction of systemic TNF alpha production.
Inhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic regulators that have attracted attention as potential targets for cancer therapeutics. Although recent studies have revealed that small-molecule IAP antagonists induce tumor selective cell death in an autocrine tumor necrosis factor (TNF)α-dependent manner, the single-agent efficacy of IAP antagonists is restricted to a small subset of cancer cells. In this study, we showed that the single-agent activity of T-3256336 was limited to a few cancer cell lines in vitro, and these cell lines were defined by relatively high levels of TNFα mRNA expression. However, some other cancer cells, including PANC-1 cells, become drastically sensitive to T-3256336 when costimulated with exogenous TNFα. In PANC-1 mouse xenograft models, the administration of T-3256336 increased levels of several cytokines including TNFα and lead to tumor regression as a single agent, which was attenuated by the neutralization of circulating mouse TNFα with an antibody. These results suggest dual roles of IAP antagonists, increase systemic cytokines including TNFα, and sensitization of tumors to IAP antagonist-induced death.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: hiroyuki.sumi@takeda.com.
Hiroyuki
H
Sumi
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masakazu
M
Inazuka
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Kentaro
K
Hashimoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Tomoyasu
T
Ishikawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Sei
S
Yoshida
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: masato.yabuki@takeda.com.
Masato
M
Yabuki
D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D011719:Pyrazines; C000607552:T-3256336; D014409:Tumor Necrosis Factor-alpha
IAP antagonist; T-3256336; TNFα; cIAP