Joon-Seok Choi

Colorectal cancer (CRC) remains difficult to treat due to challenges in early detection and the development of therapeutic resistance. Dopamine receptor D2 (DRD2) plays a critical role in regulating cell proliferation and apoptosis in various solid tumors. Given the relatively high levels of dopamine in the gastrointestinal tract, colorectal tumors may be particularly susceptible to DRD2-mediated signaling. In this study, we evaluated the anticancer activity of a newly synthesized DRD2 antagonist, SD2-2305, and investigated its underlying mechanisms in human CRC cell lines HCT116 and HT-29. SD2-2305 reduced cell viability in a time- and dose-dependent manner. Induction of apoptosis was confirmed by Annexin V/PI staining and immunoblot analysis, with activation of caspase-3, caspase-7, and caspase-9, although no significant changes were observed in the expression of Bcl-2 family proteins. Furthermore, SD2-2305 induced G1 phase cell cycle arrest, accompanied by downregulation of Cyclin A, Cyclin B, CDK1, and CDK2, and upregulation of p21. While key survival pathways (JAK2/STAT3, PI3K/Akt, and MAPK) remained relatively unaffected, SD2-2305 modulated growth factor receptors post-transcriptionally, decreasing HER2/ErbB2 and increasing TGF-beta receptor 1 expression. Collectively, these findings demonstrate that the DRD2 antagonist SD2-2305 exerts potent anticancer effects through the induction of cell cycle arrest and apoptosis, and suggest that the anticancer activity of SD2-2305 is associated with coordinated modulation of growth factor receptor signaling and cell-cycle regulators in CRC cells.

Hematopoietic progenitor kinase 1 (HPK1) is a critical negative regulator of T‐cell receptor signaling and has emerged as a promising immune checkpoint target for cancer immunotherapy. In this study, we report the design, synthesis, and structure–activity relationship (SAR) exploration of a novel series of 2,4‐diaminopyrimidine derivatives as potent HPK1 inhibitors. Systematic optimization revealed that the incorporation of an (S)‐phenylglycinol moiety and meta‐ or para‐substituted aniline groups at the scaffold significantly enhanced inhibitory potency. Among the synthesized analogs, compound 7h was identified as a lead candidate, exhibiting robust enzymatic inhibition and effectively suppressing the phosphorylation of SLP76 in cellular assays. These results demonstrate that the 2,4‐diaminopyrimidine scaffold provides a viable foundation for the development of next‐generation HPK1‐targeted immunotherapies.

Sarcopenia is an age-related condition marked by a reduction in muscle mass and strength, and it is associated with impaired muscle regeneration and differentiation. While diseases like cardiovascular and chronic liver disease can induce sarcopenia, there is limited evidence regarding the specific diseases and mechanisms responsible for its development. In skeletal muscle, the loss of muscle mass is accompanied by a decrease in myofilament proteins and the inhibition of muscle differentiation in satellite cells. Bioactive compounds obtained from natural products have been traditionally used as therapeutics for diverse conditions. In this report, we investigated the effect of cinchonidine (CD) extracted from Cinchona tree on muscle differentiation of mouse satellite cells, and myoblast cell lines. CD significantly inhibited muscle differentiation by suppressing myotube formation and gene expression of myogenesis markers. In addition, CD reduced muscle differentiation by blocking phosphorylation of insulin receptor substrate 1 (IRS-1) during insulin-induced signal transduction. Therefore, the results show that CD, an antimalarial agent, inhibited muscle differentiation through the suppression of IRS-1 phosphorylation, suggesting that sarcopenia can be induced by CD.

Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantolactone (IAL) on human CRC cells HCT116 and Ox-resistant HCT116 (HCT116-OxR). Apoptosis, ROS generation, cell cycle distribution, mitochondrial membrane potential (MMP), and caspase activation were assessed through flow cytometry. Protein levels were determined by Western blot analysis. IAL reduced cell viability, measured by MTT assay, and inhibited anchorage-independent colony formation in CRC cells in a time- and concentration-dependent manner. The IC₅₀ values for 48 h of incubation were below 10 µM. Annexin V/7-AAD double staining demonstrated that IAL induced apoptosis in HCT116 and HCT116-OxR cells, and Western blot analysis confirmed increased phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK). The inhibition of these kinases by SP600125 or SB203580 blocked the antiproliferative effects of IAL. Additionally, IAL triggered ROS generation and disrupted mitochondrial membranes, leading to caspase activation. Pretreatment with N-acetylcysteine (NAC) or Z-VAD-FMK inhibited the antiproliferative effects of IAL, highlighting the crucial roles of ROS generation and caspase activation in IAL-induced apoptosis in CRC cells. In summary, IAL exhibited anticancer effects in CRC cells by inducing apoptosis by elevating ROS level and activating JNK and p38 MAPK. These findings warrant further study to evaluate the therapeutic potential of IAL in treating CRC with various resistances.

Geumi Park, Manoj Kumar Baniya, Eun-Jeong Cha, So Jin Sim, Joon-Seok Choi, Kyung-Soo Chun. J Cancer Prev 2025;30:24-31. https://doi.org/10.15430/JCP.24.032

Sarcopenia is a disease characterized by decreased muscle fibers and mass. Although it mainly affects the older adults, it can also occur in various age groups as a secondary effect of medications used for treating certain diseases, such as cancer and diabetes. With population aging, sarcopenia has drawn significant attention owing to its increasing prevalence. However, its pathogenesis remains unclear, and no specific treatment is available. Natural products containing bioactive compounds have long been used as therapeutic agents and are crucial sources for drug development. However, the use of drugs derived from natural extracts is limited because of their ambiguous mechanisms of action and potential side effects. Therefore, a systematic analysis of the potential effects of using natural products is required. In this study, we investigated the effects of the antimalarial drug quinine on myogenic differentiation. Our findings revealed that quinine significantly inhibited the expression of marker genes and proteins associated with myogenic differentiation and markedly impaired muscle regeneration following injury. Furthermore, this reduction occurred when quinine selectively decreased the AKT signaling activity. Quinine reduced muscle protein and gene expression by modulating AKT signaling and inhibiting myogenic differentiation and muscle regeneration. Therefore, quinine may cause sarcopenia, and this risk should be considered when using quinine for treatment.

Juthika Kundu, Hobin Yang, Saerom Moon, Mi Ran Byun, Young Kee Shin, Kyoung Song and Joon-Seok Choi. Biomolecules & Therapeutics 2024;32:767-77. https://doi.org/10.4062/biomolther.2024.024

Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both alpha and beta isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

Rajina Shakya, Mi Ran Byun, Sang Hoon Joo, Kyung-Soo Chun and Joon-Seok Choi. Biomolecules & Therapeutics 2023;31:692-9. https://doi.org/10.4062/biomolther.2023.173

Rajina Shakya, Gyu Hwan Park, Sang Hoon Joo, Jung-Hyun Shim and Joon-Seok Choi. Biomolecules & Therapeutics 2022;30:585-92. https://doi.org/10.4062/biomolther.2022.121