Small molecule inhibitors from organoid‐based drug screen induce concurrent apoptosis and gasdermin E‐dependent pyroptosis in colorectal cancer

Zhang, Yuchen; Xu, Zhuoqing; Feng, Wenqing; Gao, Han; Xu, Zifeng; Miao, Yiming; Li, Wenchang; Chen, Fangqian; Lv, Zeping; Huo, Jianting; Tuersun, Abudumaimaitijiang; Liu, Wang-Yi; Zong, Yaping; Shen, Xiaohui; Zhao, Jingkun; Liu, Aiguo

doi:10.1002/ctm2.812

Cited by 17 publications

(15 citation statements)

References 8 publications

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“…We previously found BI 2536 induced concurrent apoptosis and pyroptosis in colorectal cancer cells ( 13 ). Here, we observed the morphology of BI 2536-treated A2780 cells.…”

Section: Resultsmentioning

confidence: 98%

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BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

et al. 2022

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BackgroundThe frequent emergence of drug resistance to chemotherapy is a major obstacle for the treatment of ovarian cancer. There is a need for novel drugs to fulfill this challenge. Pyroptosis-inducing drugs can inhibit tumor growth. However, their roles in ovarian cancer have not been demonstrated.MethodsWe tested the effectiveness of a novel drug, BI 2536, which we found in colorectal cancer. Cell proliferation, cell cycle, and drug-induced apoptosis and pyroptosis were tested. In vivo treatments were performed using a cell-derived xenograft model.ResultsBI 2536 significantly inhibited the proliferation of ovarian cancer cells and induced cell cycle arrest at the G2/M phases. After BI 2536 treatment, DNA fragmentation and PS exposure on the outside of apoptotic cells were detected. Moreover, the pyroptotic phenotype of ovarian cancer cells along with the release of LDH and HMGB1 were observed, indicating the leakage of cells. Western blot analysis verified that BI 2536 induced GSDME-mediated pyroptosis. Pyroptosis was abolished after additional treatment with Z-DEVD-FMK, a caspase-3 inhibitor. Thus, BI 2536 induced pyroptosis in ovarian cancer through the caspase-3/GSDME pathway. In vivo experiments further demonstrated the antitumoral effect and ability of BI 2536 to accumulate CD8+ T cells in ovarian cancer.ConclusionIn this study, we identified BI 2536 as an effective anti-ovarian cancer drug that inhibits proliferation, arrests the cell cycle, induces apoptosis and pyroptosis, and leads to the accumulation of CD8+ T cells in tumor sites. Drug-induced pyroptosis may have promising prospects for reducing side effects and activating immune responses.

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“…We previously found BI 2536 induced concurrent apoptosis and pyroptosis in colorectal cancer cells ( 13 ). Here, we observed the morphology of BI 2536-treated A2780 cells.…”

Section: Resultsmentioning

confidence: 98%

“…Previously, we found a novel small molecule inhibitor, BI 2536, which can induce GSDME-mediated pyroptosis in colorectal cancer ( 13 ). Since there are few studies on the role of pyroptosis in ovarian cancer, we wondered whether BI 2536 could have a similar antitumor effect in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

et al. 2022

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“…It also delayed cancer progression in the H460 tumour model in mice 7 . In the third study, the authors established an organoid model to screen a small molecule compound library 8 . The authors found that 4 SMIs, bortezomib, obatoclax mesylate, BI 2536 (BI) and (S)‐(+)‐camptothecin (CPT), all exhibited antitumor effects through induction of apoptosis.…”

Section: Smis Induce Icd and May Overcome Drug Resistancementioning

confidence: 99%

“…7 In the third study, the authors established an organoid model to screen a small molecule compound library. 8 The authors found that 4 SMIs, bortezomib, obatoclax mesylate, BI 2536 (BI) and (S)-(+)-camptothecin (CPT), all exhibited antitumor effects through induction of apoptosis. However, BI and CPT also induced gasdermin E-dependent pyroptosis.…”

Section: Smis Induce Icd and May Overcome Drug Resistancementioning

confidence: 99%

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Immunogenic cell death‐inducing small molecule inhibitors: Potential for immunotherapy of cancer

Guo

Kaliński

Chen

et al. 2022

Clinical and Translational Dis

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Small molecule inhibitors (SMIs) of key signalling pathways are known to induce multiple types of regulated cell death, including immunogenic cell death (ICD). The resulting antitumor immunity helps to overcome the resistance of cancer cells to cell death, resulting in improved cancer therapy. SMIs, especially those inducing multimodal cell death and ICD, can be critical components in rational combinations for cancer immunotherapy.

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Identification of prognostic biomarkers for cervical cancer based on programmed cell death‐related genes and assessment of their immune profile and response to drug therapy

Feng,

Wang,

Zhang

et al. 2023

The Journal of Gene Medicine

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BackgroundProgrammed cell death (PCD) has been widely investigated in various human diseases. The present study aimed to identify a novel PCD‐related genetic signature in cervical squamous cell carcinoma (CESC) to provide clues for survival, immunotherapy and drug sensitization prediction.MethodsSingle‐sample gene set enrichment analysis (ssGSEA) was used to quantify the PCD score and assess the distribution of PCD in clinicopathological characteristics in The Cancer Genome Atlas (TCGA)‐CESC samples. Then, the ConsensusClusterPlus method was used to identify molecular subtypes in the TCGA‐CESC database. Genomic mutation analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment, as well as tumor microenvironment (TME) infiltration analysis, were performed for each molecular subtype group. Finally, a prognostic model by Uni‐Cox and least absolute shrinkage and selection operator‐Cox analysis was established based on differentially expressed genes from molecular subtypes. ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) and ssGSEA were performed to assess the correlation between the model and TME. Drug sensitization prediction was carried out with the oncoPredict package.ResultsPreliminary analysis indicated that PCD had a potential association clinical characteristics of the TCGA‐CESC cohort, and PCD‐related genes mutated in 289 (70.59%) CESC patients. Next, four groups of CESC molecular typing were clustered based on 63 significantly prognostic PCD‐related genes. Among four subtypes, C1 group displayed the worst prognosis combined with over expressed PCD genes and enriched cell cycle‐related pathways. C4 group exhibited the best prognosis accompanied with high degree of immune infiltration. Finally, a five‐gene (SERPINE1, TNF, CA9, CX3CL1 and JAK3) prognostic model was constructed. Patients in the high‐risk group displayed unfavorable survival. Immune infiltration analysis found that the low‐risk group had significantly higher levels of immune cell infiltration such as T cells, Macrophages_M1, relative to the high‐risk group, and were significantly enriched in apoptosis‐associated pathways, which predicted a higher level of immunity. Drug sensitivity correlation analysis revealed that the high‐risk group was resistant to conventional chemotherapeutic drugs and sensitive to the Food and Drug Administration‐approved drugs BI.2536_1086 and SCH772984_1564.ConclusionsIn the present study, we first found that PCD‐related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five‐PCD‐associated‐gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug‐sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

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Small molecule inhibitors from organoid‐based drug screen induce concurrent apoptosis and gasdermin E‐dependent pyroptosis in colorectal cancer

Cited by 17 publications

References 8 publications

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer

Immunogenic cell death‐inducing small molecule inhibitors: Potential for immunotherapy of cancer

Identification of prognostic biomarkers for cervical cancer based on programmed cell death‐related genes and assessment of their immune profile and response to drug therapy

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