Di-indenopyridines as topoisomerase II-selective anticancer agents: Design, synthesis, and structure-activity relationships.

Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/IIα inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo IIα inhibition at 20 µM concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo IIα inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo IIα inhibitors with remarkable anticancer effects.

Chalcone: A potential scaffold for NLRP3 inflammasome inhibitors.

Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1ß and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions. However, none of the known NLRP3 inhibitors has been approved for clinical use. Sulfonylurea and covalent inhibitors with electrophilic warhead (Michael acceptor) are among the prominent classes of compounds explored for their NLRP3 inhibitory effects. Chalcone, a small molecule with α, ß unsaturated carbonyl group (Michael acceptor), has also been studied as a promising scaffold for the development of NLRP3 inhibitors. Low molecular weight, easy to manipulate lipophilicity and cost-effectiveness have attracted many to use chalcone scaffold for drug development. In this review, we highlight chalcone derivatives with NLRP3 inflammasome inhibitory activities. Recent developments and potential new directions summarized here will, hopefully, serve as valuable perspectives for investigators including medicinal chemists and drug discovery researchers to utilize chalcone as a scaffold for developing novel NLRP3 inflammasome inhibitors.

Chemical inhibition of TRAF6-TAK1 axis as therapeutic strategy of endotoxin-induced liver disease.

The liver is exposed to gut-derived bacterial endotoxin via portal circulation, and recognizes it through toll-like receptor 4 (TLR4). Endotoxin lipopolysaccharide (LPS) stimulates the self-ubiquitination of ubiquitin ligase TRAF6, which is linked to scaffold with protein kinase TAK1 for auto-phosphorylation and subsequent activation. TAK1 activity is a signal transducer in the activating pathways of transcription factors NF-κB and AP-1 for production of various cytokines. Here, we hypothesized that TRAF6-TAK1 axis would be implicated in endotoxin-induced liver disease. Following exposure to endotoxin LPS, TLR4-mediated phosphorylation of TAK1 and transcription of cell-death cytokine TNF-α were triggered in Kupffer cells but not in hepatocytes as well as TNF receptor-mediated and caspase-3-executed apoptosis was occurred in D-galactosamine (GalN)-sensitized hepatocytes under co-culture with Kupffer cells. Treatment with pyridinylmethylene benzothiophene (PMBT) improved endotoxin LPS-induced hepatocyte apoptosis in GalN-sensitized C57BL/6 mice via suppressing NF-κB- and AP-1-regulated expression of TNF-α in Kupffer cells, and rescued the mice from hepatic damage-associated bleeding and death. As a mechanism, PMBT directly inhibited Lys 63-linked ubiquitination of TRAF6, and mitigated scaffold assembly between TRAF6 and the TAK1-activator adaptors TAB1 and TAB2 complex in Kupffer cells. Thereby, PMBT interrupted TRAF6 ubiquitination-induced activation of TAK1 activity in the TLR4-mediated signal cascade leading to TNF-α production. However, PMBT did not directly affect the apoptotic activity of TNF-α on GalN-sensitized hepatocytes. Finally, we propose chemical inhibition of TRAF6-TAK1 axis in Kupffer cells as a strategy for treating liver disease due to gut-derived endotoxin or Gram-negative bacterial infection.

Potent inhibitory activity of hydroxylated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones on LPS-stimulated reactive oxygen species production in RAW 264.7 macrophages.

This study attempted to discover tetralone-derived potent ROS inhibitors by synthesizing sixty-six hydroxylated and halogenated 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones via Claisen-Schmidt condensation reaction. The majority of the synthesized and investigated compounds significantly inhibited ROS in LPS-stimulated RAW 264.7 macrophages. When compared to malvidin (IC50 = 9.00 µM), compound 28 (IC50 = 0.18 µM) possessing 6­hydroxyl and 2­trifluoromethylphenyl moiety showed the most potent ROS inhibition. In addition, the compounds 20, 31, 39, 45, 47-48, 52, 55-56, 58-60, and 62 also displayed ten folds greater ROS inhibitory activity relative to the reference compound. Based on the structure-activity relationship study, incorporating hydroxyl groups at the 6- and 7-positions of tetralone scaffold along with different halogen functionalities in phenyl ring B is crucial for potent ROS suppression. This study contributes to a better understanding of the effect of halogen and phenolic groups in ROS suppression, and further investigations on 2-benzylidene-3,4-dihydronaphthalen-1(2H)-ones will potentially lead to the discovery of effective anti-inflammatory agents.

Significance of Altered Fatty Acid Transporter Expressions in Uterine Cervical Cancer and Its Precursor Lesions.

BACKGROUND: High-risk human papilloma virus (HR HPV) infection is a major factor leading to the development of uterine cervical cancer. Data suggest that alterations in lipid metabolism are related to the pathogenesis of cervical cancer. Specifically, the uptake of exogenous fatty acids and their intracellular storage in lipid droplets enables cancer cells to survive and adapt to the changing tumor environment. MATERIALS AND METHODS: We compared the immunohistochemical expression of fatty acid transport protein 4 (FATP4), and cluster of differentiation 36/fatty acid translocase (CD36/FAT) in normal cervical epithelium, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) tissues of the uterine cervix. We also investigated the clinicopathological implications of these fatty acid transporters in SCC. RESULTS: Compared with that in normal cervical tissues, the expression of FATP4 was lower in LSIL (p=0.002), HSIL (p=0.006), and SCC (p=0.001). In contrast, CD36 expression was higher in SCC tissues than in normal cervical tissues (p<0.001). In normal cervical tissues, HR HPV-infected lesions exhibited a decrease in FATP4 (p<0.001) and an increase of CD36 (p=0.134), compared to those that were not infected with HR HPV. High CD36 expression was associated with a shorter recurrence-free survival (p<0.001). However, high FATP4 levels showed no significant correlation with the clinicopathological parameters of SCC. CONCLUSION: Altered expression levels of FATP4 and CD36 are unique features that might be related to HR HPV infection and promote tumorigenesis and progression of cervical cancer.

Topoisomerase IIα inhibitory and antiproliferative activity of dihydroxylated 2,6-diphenyl-4-fluorophenylpyridines: Design, synthesis, and structure-activity relationships.

A new series of fifty-four 2-phenol-4-aryl-6-hydroxyphenylpyridines containing fluorophenyl, trifluoromethylphenyl, and trifluoromethoxy phenyl groups were synthesized and tested for topoisomerase IIα inhibitory and antiproliferative activity against different cancer cell lines in an attempt to look into topoisomerase IIα-targeted prospective anticancer agents to counter the limitations of available treatment options. When compared to positive controls, several compounds 11-12, 37, 50, and 51 showed high antiproliferative activity, while several 4-fluorophenyl substituted compounds 13-14 and 18 showed strong topoisomerase IIα inhibition. Surprisingly, most of the compounds had a significant antiproliferative effect on the HCT15 colorectal adenocarcinoma and T47D breast cancer cell lines. Moreover, compound 12 with para-fluorophenyl at the 4-position and meta-phenolic groups at the 2- and 6-positions inhibited proliferating HeLa cervix adenocarcinoma cells with an IC50 value of 1.28 µM. Based on biological results, the structure-activity relationships of the synthesized derivatives emphasized the significance of 4-trifluoromethoxyphenyl groups for strong antiproliferative activity and 4-fluorophenyl groups for strong topo IIα inhibition. Furthermore, meta- and para-phenolic groups at the 2- and 4-positions are favorable for strong topo IIα inhibitory and antiproliferative activity. The research findings provide insight into the effect of different fluorine functionalities in the discovery of novel topoisomerase IIα-targeted anticancer agents.

Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors.

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF3- and OCF3-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF3- groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.

AK-I-190, a New Catalytic Inhibitor of Topoisomerase II with Anti-Proliferative and Pro-Apoptotic Activity on Androgen-Negative Prostate Cancer Cells.

Castration-resistant prostate cancer (CRPC) is a clinical challenge in treatment because of its aggressive nature and resistance to androgen deprivation therapy. Topoisomerase II catalytic inhibitors have been suggested as a strategy to overcome these issues. We previously reported AK-I-190 as a novel topoisomerase II inhibitor. In this study, the mechanism of AK-I-190 was clarified using various types of spectroscopic and biological evaluations. AK-I-190 showed potent topoisomerase II inhibitory activity through intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in significantly less DNA toxicity than etoposide, a clinically used topoisomerase II poison. AK-I-190 induced G1 arrest and effectively inhibited cell proliferation and colony formation in combination with paclitaxel in an androgen receptor-negative CRPC cell line. Our results confirmed that topoisomerase II catalytic inhibition inhibited proliferation and induced apoptosis of AR-independently growing prostate cancer cells. These findings indicate the clinical relevance of topoisomerase II catalytic inhibitors in androgen receptor-negative prostate cancer.

Discovery of a 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amine derivative as a novel DNA intercalating topoisomerase IIα poison.

Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with -CF3 and -OCF3 substituents at 4- position and 3' or 4'-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.

4-Flourophenyl-substituted 5H-indeno[1,2-b]pyridinols with enhanced topoisomerase IIα inhibitory activity: Synthesis, biological evaluation, and structure-activity relationships.

A series of fluorinated and hydroxylated 2,4-diphenyl indenopyridinols were designed and synthesized using l-proline-catalyzed and microwave-assisted synthetic methods for the development of new anticancer agents. Adriamycin and etoposide were used as reference compounds for the evaluation of topo IIα inhibitory and anti-proliferative activity of the synthesized compounds. Exploring the structure-activity relationships of 36 prepared compounds and biological results, most of the compounds with ortho- and para-fluorophenyl at 4-position of indenopyridinol ring displayed strong topo IIα inhibition. In addition, the majority of the ortho- and meta-fluorophenyl substituted compounds 1-24 displayed strong anti-proliferative activity against DU145 prostate cancer cell line compared to the positive controls. Interestingly, compound 4 possessing ortho-phenolic and ortho-fluorophenyl group at 2- and 4-position, respectively of the central pyridine ring showed high anti-proliferative activity (IC50 = 0.82 µM) against T47D human breast cancer cell line, while para-phenolic and para-fluorophenyl substituted compound 36 exhibited potent topo IIα inhibitory activity with 94.7% and 88.6% inhibition at 100 µM and 20 µM concentration, respectively. A systematic comparison between the results of this study and the previous study indicated that minor changes in the position of functional groups in the structure affect the topo IIα inhibitory activity and anti-proliferative activity of the compounds. The findings from this study will provide valuable information to the researchers working on the medicinal chemistry of topoisomerase IIα-targeted anticancer agents.

Upregulation of Fatty Acid Transporters is Associated With Tumor Progression in Non-Muscle-Invasive Bladder Cancer.

As patients with non-muscle-invasive bladder cancer (NMIBC) show a high degree of heterogeneity in tumor recurrence or progression, many clinicians demand a detailed risk stratification. Although modified fatty acid metabolism in cancer cells is reported to reflect malignant phenotypes such as metastasis, the impact of fatty acid transporters on NMIBC has never been investigated. This study examined the clinicopathologic implications of fatty acid transporters such as fatty acid transport protein 4 (FATP4), cluster of differentiation 36/fatty acid translocase (CD36/FAT), and long chain acyl CoA synthetase 1 (ACSL1) in 286 NMIBC cases. This study revealed that FATP4, CD36, and ACSL1 were overexpressed in 123 (43.0%), 43 (15.0%), and 35 (12.2%) NMIBC cases, respectively. High FATP4 in tumor cells was associated with high grade (p = 0.004) and high stage (p = 0.039). High CD36 was related to high grade (p < 0.001), high stage (p = 0.002), and non-papillary growth type (p = 0.004). High ACSL1 showed an association with high grade (p < 0.001), high stage (p = 0.01), non-papillary growth type (p = 0.002), and metastasis (p = 0.033). High FATP4 was an independent factor predicting short overall survival (OS) (hazard ratio = 3.32; 95% confidence interval, 1.07-10.31; p = 0.038). In conclusion, upregulation of FATP4, CD36, and ACSL1 might promote the NMIBC progression and could be exploited in clinical risk stratification and targeted therapy.

Increased expression levels of AURKA and KIFC1 are promising predictors of progression and poor survival associated with gastric cancer.

Increased cell proliferation is a critical hallmark of cancer development and progression. The proliferation of tumor cells depends on mitotic deregulation. Here, we identified the differentially expressed genes (DEGs) in gastric cancer (GC) through RNA sequencing data and bioinformatics analysis. Subsequent functional and pathway enrichment analyses showed that the screened DEGs were enriched in the mitosis-associated pathway. Based on the analysis results, we selected two signatures (aurora kinase A [AURKA] and kinesin family member C1 [KIFC1]) to determine their clinicopathological significance. The results showed a significant positive correlation between AURKA and KIFC1 expression both at the mRNA and protein levels. AURKA expression was positively correlated with distant metastases (p = 0.032) and tumor-node-metastasis (TNM) stage (p = 0.001). Elevated KIFC1 expression was significantly associated with tumor size (p = 0.029), depth of invasion (p < 0.001), lymph node metastasis (p < 0.001), distant metastasis (p = 0.023), and TNM stage (p < 0.001). Higher AURKA (hazard ratio [HR] = 1.3, p < 0.001) and KIFC1 (HR = 1.41, p < 0.001) mRNA levels were also significantly correlated with poor overall survival. Thus, AURKA and KIFC1 could serve as potential prognostic markers and therapeutic targets for GC.

Anticancer Activity of Indeno[1,2-b]-Pyridinol Derivative as a New DNA Minor Groove Binding Catalytic Inhibitor of Topoisomerase IIα.

Topoisomerase IIα has been a representative anti-cancer target for decades thanks to its functional necessity in highly proliferative cancer cells. As type of topoisomerase IIα targeting drugs, topoisomerase II poisons are frequently in clinical usage. However, topoisomerase II poisons result in crucial consequences resulted from mechanistically induced DNA toxicity. For this reason, it is needed to develop catalytic inhibitors of topoisomerase IIα through the alternative mechanism of enzymatic regulation. As a catalytic inhibitor of topoisomerase IIα, AK-I-191 was previously reported for its enzyme inhibitory activity. In this study, we clarified the mechanism of AK-I-191 and conducted various types of spectroscopic and biological evaluations for deeper understanding of its mechanism of action. Conclusively, AK-I-191 represented potent topoisomerase IIα inhibitory activity through binding to minor groove of DNA double helix and showed synergistic effects with tamoxifen in antiproliferative activity.

Synthesis and structure-activity relationships of hydroxylated and halogenated 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols as selective topoisomerase IIα inhibitors.

The objective of this study was to discover potential topoisomerase (topo) targeting anticancer agents. Novel series of hydroxylated and halogenated(-F, -Cl, and -CF3) 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols were systematically designed and synthesized by faster, economic, and environmentally friendly l-proline catalyzed and microwave-assisted one pot reaction method. The synthesized compounds were assessed for topo I and IIα inhibitory and anti-proliferative activities. The in vitroevaluation displayed that most of the compounds have selective topo IIα inhibitoryactivity as well as selectivity towards T47D human cancer cell line. Structure-activity relationship study suggested that the introduction of additional hydroxyl functionality at 7-positon of benzofuro[3,2-b]pyridine skeleton is crucial for selective topo IIα inhibitory activity. Placement of phenolic moiety on the 4-position of the tricyclic system imparts better topo IIα inhibitory and anti-proliferative activity.

Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer's disease.

Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with α, ß unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer's disease (AD). Small molecular size, convenient and cost-effective synthesis, and flexibility for modifications to modulate lipophilicity suitable for blood brain barrier (BBB) permeability make chalcones a preferred candidate for their therapeutic and diagnostic potential in AD. This review summarizes and highlights the importance of chalcone and its analogs as single target small therapeutic agents, multi-target directed ligands (MTDLs) as well as molecular imaging agents for AD. The information summarized here will guide many medicinal chemist and researchers involved in drug discovery to consider chalcone as a potential scaffold for the development of anti-AD agents including theranostics.

Selective inhibitory effects of HYIpro-3-1 on CYP1A2 in human liver microsomes.

CYP1A2 is one of the main Cytochrome P450 enzymes in the human liver associated with the metabolism of several xenobiotics. CYP1A2 is especially involved in the metabolic activation of different procarcinogens. Therefore, the development of cancer may be inhibited by inhibiting CYP1A2 activity. Here, the inhibitory effect of HYIpro-3-1 and its derivatives on CYP1A2 activity in human liver microsomes (HLM) was studied through LC-MS/MS using a cocktail assay. Among the four compounds, HYIpro-3-1 showed the most selective and strongest inhibitory effect on CYP1A2 at IC50 values of 0.1 µM in HLMs and inhibition was confirmed using purified human CYP1A2. It was determined that inhibition is reversible because the inhibitory effect of HYIpro-3-1 is not dependent on preincubation time. HYIpro-3-1 showed a typical pattern of competitive inhibition for CYP1A2-catalyzed phenacetin O-deethylation, based on the Lineweaver-Burk plot, with a Ki value of 0.05 µM in HLMs; the secondary plot also showed a linear pattern. In our study, HYIpro-3-1 was proposed as a novel inhibitor with the capacity to selectively inhibit CYP1A activity in HLMs.

Correction: Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: Involvement of p53/FoxO3A axis.

[This corrects the article DOI: 10.18632/oncotarget.3347.].

Increased HOXC6 mRNA expression is a novel biomarker of gastric cancer.

In this study, we aimed to investigate the molecular biomarkers that are pivotal for the development and progression of gastric cancer (GC). We analyzed clinical specimens using RNA sequencing to identify the target genes. We found that the expression of HOXC6 mRNA was upregulated with the progression of cancer, which was validated by quantitative real time PCR and RNA in-situ hybridization. To compare the protein expression of HOXC6, we evaluated GC and normal gastric tissue samples using western blot analysis and immunohistochemistry. We detected significantly higher levels of HOXC6 in the GC tissues than in the normal controls at both mRNA and protein levels. The expression levels of HOXC6 mRNA in patients with advanced gastric cancer (AGC) were significantly higher than those in patients with early gastric cancer (EGC). Kaplan-Meier curves showed that high expression of HOXC6 mRNA is significantly associated with poor clinical prognosis. Our findings suggest that HOXC6 mRNA may be a novel biomarker and can be potentially valuable in predicting the prognosis of GC patients. Especially, HOXC6 mRNA in-situ hybridization may be a diagnostic tool for predicting prognosis of individual GC patients.

Protein expression profiles and prognostic value of E2F family members in clear cell renal cell carcinoma.

The derangement of the cell cycle facilitates uncontrolled cell proliferation and acquisition of genetic alterations favorable for malignancy. However, the protein expression profiles of E2 F family cell cycle regulators in clear cell renal cell carcinoma (ccRCC) have not yet been thoroughly investigated. In this study, we aimed to examine the protein expression profiles and prognostic value of E2 F1, E2 F3, and E2 F4 in ccRCC cases. The immunohistochemical expression of E2 F1, E2 F3, and E2 F4 was quantitatively scored in 180 ccRCC tumor tissues and 79 normal kidney tissues. The prognostic implications of these E2 F members were determined. We found that ccRCC tumor cells showed higher nuclear expression of E2 F1, E2 F3 and E2 F4 than normal kidney samples. High E2 F1 and E2 F3 expression in tumor cells was associated with poor prognostic factors of ccRCC, whereas high E2 F4 correlated with beneficial prognostic factors. High expression of E2 F1 and E2 F3 in tumor cells was correlated with a poor overall and recurrence-free survival, while high E2 F4 expression did not. In conclusion, E2 F1, E2 F3 and E2 F4 may function as oncogenes during tumorigenesis of ccRCC, although they contribute to the progression of ccRCC in different ways. Additional studies are required to clarify the conflicting role of E2 F4 in the tumor evolution of ccRCC.

Kikuchi Disease Manifesting as Multifocal Lymphadenopathy and Splenomegaly: Ultrasonography, CT, and 18F-FDG PET/CT Findings Mimicking Lymphoma.

Kikuchi disease is a type of benign, self-limiting necrotizing lymphadenitis that occurs most commonly in young women and usually manifests as palpable cervical lymph nodes and fever. Patients with an unusual location of lymph node involvement can be misdiagnosed with malignant disease. Here, we report a case of Kikuchi disease in a 15-year-old girl presenting with persistent fever for 2 weeks. Imaging studies, including ultrasonography, CT, and 18F-fluorodeoxyglucose PET/CT, revealed splenomegaly and enlarged lymph nodes in the neck, axilla, abdomen, retroperitoneum, and inguinal region. Laparoscopic excision of the celiac lymph nodes confirmed histiocytic necrotizing lymphadenitis, also known as Kikuchi disease. Conservative treatment with corticosteroids improved the patient's condition.