title: Induction of immunogenic cell death of tumors by newly synthesized heterocyclic quinone derivative.
abstract: Many cancer types are serious diseases causing mortality, and new therapeutics with improved efficacy and safety are required. Immuno-(cell)-therapy is considered as one of the promising therapeutic strategies for curing intractable cancer. In this study, we tested R2016, a newly developed heterocyclic quinone derivative, for induction of immunogenic tumor cell death and as a possible novel immunochemotherapeutic. We studied the anti-cancer effects of R2016 against LLC, a lung cancer cell line and B16F10, a melanoma cell line. LLC (non-immunogenic) and B16F10 (immunogenic) cells were killed by R2016 in dose-dependent manner. R2016 reduced the viability of both LLC and B16F10 tumor cells by inducing apoptosis and necrosis, while it demonstrated no cytotoxicity against normal splenocytes. Expression of immunogenic death markers on the cell surface of R2016 treated tumor cells including calreticulin (CRT) and heat shock proteins (HSPs) was increased along with the induction of their genes. Increased CRT expression correlated with dendritic cell (DC) uptake of dying tumor cells: the proportion of CRT+CD11c+cells was increased in the R2016-treated group. The gene transcription of Calr3, Hspb1, and Tnfaip6, which are related to immunogenicity induction of dead cells, was up-regulated in the R2016 treated tumor cells. On the other hand, ANGPT1, FGF7, and URGCP gene levels were down-regulated by R2016 treatment. This data suggests that R2016 induced immunogenic tumor cell death, and suggests R2016 as an effective anti-tumor immunochemotherapeutic modality.
authors.affiliation: R&D Center, Pharmicell Co. Ltd., Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Keum-Joo
authors.initials: KJ
authors.lastname: Son
authors.affiliation: R&D Center, Pharmicell Co. Ltd., Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ki Ryung
authors.initials: KR
authors.lastname: Choi
authors.affiliation: College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seodaemun-ku, Seoul, Republic of Korea.
authors.forename: Chung-Kyu
authors.initials: CK
authors.lastname: Ryu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Jeju National University School of Medicine, Jeju-si, Jeju-do, Republic of Korea.
authors.forename: Seog Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seodaemun-ku, Seoul, Republic of Korea.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: R&D Center, Pharmicell Co. Ltd., Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hyunah
authors.identifier: http://orcid.org/0000-0003-2188-9729
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D039521:CD11c Antigen / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D039521:CD11c Antigen; D037282:Calreticulin; D002227:Carbazoles; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006360:Heat-Shock Proteins; D006571:Heterocyclic Compounds; D011809:Quinones; C000622185:R2016