期刊
CANCER SCIENCE
卷 109, 期 9, 页码 2687-2696出版社
WILEY
DOI: 10.1111/cas.13726
关键词
anticancer drug; cancer immunity; cytotoxicity; STING; type I interferon
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- AMED (Japan Agency for Medical Research and Development) [JP17ek0109107, JP18ek0109319, JP20gm6110008]
- Uehara Memorial Foundation
- Japan Rheumatism Foundation
- Princess Takamatsu Cancer Research Fund
- BONAC Corporation
- Kyowa Hakko Kirin Co., Ltd
- [JP15H05787]
Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T-cell responses and, as a result, can evoke potent antitumor immune responses. Herein, we present a novel compound N-{3-[(1,4-bipiperidin)-1-yl]propyl}-6-[4-(4-methylpiperazin-1-yl)phenyl]picolinamide (SINCRO; STING-mediated interferon-inducing and cytotoxic reagent, original) as an anticancer drug that activates the cytosolic DNA-sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN- gene induction by SINCRO is abolished in STING-deficient cells. In addition to its IFN-inducing activity, SINCRO shows STING-independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double-strand break or caspase-3 cleavage. Thus, SINCRO induces cell death in a method different from conventional apoptosis-inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates invivo tumor growth by both type I IFN-dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy.
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