The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis

Go Seokhyeong,강미경,Kwon Sung Pil,정문교,전옥희,김병수 한국조직공학과 재생의학회 2021 조직공학과 재생의학 Vol.18 No.5

BACKGROUND Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. METHODS Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTS At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells. CONCLUSION The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.

The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis

Seokhyeong GO,Mikyung KANG,Sung Pil KWON,Mungyo JUNG,Ok Hee JEON,Byung?Soo KIM 한국생물공학회 2021 한국생물공학회 학술대회 Vol.2021 No.10

Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. We treated bleomycin-indueced senescent human dermal fibroblasts(HDFs) with JQ1 and determined whether JQ1 has senolytic effects with ferroptosis. At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability and decreased SASP expression of senescent cells but did not reduce that of non-senescent cells, indicating that JQ1 treatment can selectively eliminate senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes and induced lipid peroxidation only in senescent cells. It suggested ferroptosis occurred in JQ1’s senolytic pathway. So, these data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.

Immunomodulation for Tissue Repair and Regeneration

문상준,Hong Jihye,Go Seokhyeong,Kim Byung-Soo 한국조직공학과 재생의학회 2023 조직공학과 재생의학 Vol.20 No.3

Various immune cells participate in repair and regeneration following tissue injury or damage, orchestrating tissue inflammation and regeneration processes. A deeper understanding of the immune system’s involvement in tissue repair and regeneration is critical for the development of successful reparatory and regenerative strategies. Here we review recent technologies that facilitate cell-based and biomaterial-based modulation of the immune systems for tissue repair and regeneration. First, we summarize the roles of various types of immune cells in tissue repair. Second, we review the principle, examples, and limitations of regulatory T (Treg) cell-based therapy, a representative cell-based immunotherapy. Finally, we discuss biomaterial-based immunotherapy strategies that aim to modulate immune cells using various biomaterials for tissue repair and regeneration.

Senescent cancer cell-derived nanovesicle as a personalized therapeutic cancer vaccine

Hong Jihye,Jung Mungyo,Kim Cheesue,Kang Mikyung,Go Seokhyeong,Sohn Heesu,Moon Sangjun,Kwon Sungpil,Song Seuk Young,Kim Byung-Soo 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

The development of therapeutic cancer vaccines (TCVs) that provide clinical benefits is challenging mainly due to difficulties in identifying immunogenic tumor antigens and effectively inducing antitumor immunity. Furthermore, there is an urgent need for personalized TCVs because only a limited number of tumor antigens are shared among cancer patients. Several autologous nanovaccines that do not require the identification of immunogenic tumor antigens have been proposed as personalized TCVs. However, these nanovaccines generally require exogenous adjuvants (e.g., Toll-like receptor agonists) to improve vaccine immunogenicity, which raises safety concerns. Here, we present senescent cancer cell-derived nanovesicle (SCCNV) as a personalized TCV that provides patient-specific tumor antigens and improved vaccine immunogenicity without the use of exogenous adjuvants. SCCNVs are prepared by inducing senescence in cancer cells ex vivo and subsequently extruding the senescent cancer cells through nanoporous membranes. In the clinical setting, SCCNVs can be prepared from autologous cancer cells from the blood of liquid tumor patients or from tumors surgically removed from solid cancer patients. SCCNVs also contain interferon-γ and tumor necrosis factor-α, which are expressed during senescence. These endogenous cytokines act as adjuvants and enhance vaccine immunogenicity, avoiding the need for exogenous adjuvants. Intradermally injected SCCNVs effectively activate dendritic cells and tumor-specific T cells and inhibit primary and metastatic tumor growth and tumor recurrence. SCCNV therapy showed an efficacy similar to that of immune checkpoint blockade (ICB) therapy and synergized with ICB. SCCNVs, which can be prepared using a simple and facile procedure, show potential as personalized TCVs.

M1 Macrophage-Derived Nanovesicles Potentiate the Anticancer Efficacy of Immune Checkpoint Inhibitors

Choo, Yeon Woong,Kang, Mikyung,Kim, Han Young,Han, Jin,Kang, Seokyung,Lee, Ju-Ro,Jeong, Gun-Jae,Kwon, Sung Pil,Song, Seuk Young,Go, Seokhyeong,Jung, Mungyo,Hong, Jihye,Kim, Byung-Soo American Chemical Society 2018 ACS NANO Vol.12 No.9

<P>Cancer immunotherapy modulates immune cells to induce antitumor immune responses. Tumors employ immune checkpoints to evade immune cell attacks. Immune checkpoint inhibitors such as anti-PD-L1 antibody (aPD-L1), which is being used clinically for cancer treatments, can block immune checkpoints so that the immune system can attack tumors. However, immune checkpoint inhibitor therapy may be hampered by polarization of macrophages within the tumor microenvironment (TME) into M2 tumor-associated macrophages (TAMs), which suppress antitumor immune responses and promote tumor growth by releasing anti-inflammatory cytokines and angiogenic factors. In this study, we used exosome-mimetic nanovesicles derived from M1 macrophages (M1NVs) to repolarize M2 TAMs to M1 macrophages that release pro-inflammatory cytokines and induce antitumor immune responses and investigated whether the macrophage repolarization can potentiate the anticancer efficacy of aPD-L1. M1NV treatment induced successful polarization of M2 macrophages to M1 macrophages <I>in vitro</I> and <I>in vivo</I>. Intravenous injection of M1NVs into tumor-bearing mice suppressed tumor growth. Importantly, injection of a combination of M1NVs and aPD-L1 further reduced the tumor size, compared to the injection of either M1NVs or aPD-L1 alone. Thus, our study indicates that M1NV injection can repolarize M2 TAMs to M1 macrophages and potentiate antitumor efficacy of the checkpoint inhibitor therapy.</P> [FIG OMISSION]</BR>