Target identification and drug discovery by data-driven hypothesis and experimental validation in ovarian endometriosis

Yin M, Minuo Yin, Zhang J, Jiaming Zhang, Zeng X, Xinliu Zeng, Hanke Zhang, Zhang H, Ying Gao, Gao Y
Fertility and sterility · 2021 · vol. 116(2) , pp. 478–492 · doi:10.1016/j.fertnstert.2021.01.027 · PMID:33714537 · W3135620369
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This study identifies novel targets for ovarian endometriosis through data-driven hypothesis generation and experimental validation to guide drug discovery.

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Abstract

ObjectiveTo identify targets and discover drugs for ovarian endometriosis (OE) DESIGN: A basic study based on a data-driven hypothesis and experimental validation SETTING: Center for Reproductive Medicine PATIENT(S)/ANIMAL(S): Fourteen patients with OE and 7 healthy donors were recruited, and 15 female C57/BL6 mice were involved.Intervention(s)Samples of OE lesions and normal endometrium were obtained. The ITPR1-knockdowned ectopic human endometrial stromal cells (HESCs) were subjected to ribonucleic acid (RNA) sequencing, cell-counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, and flow cytometry. Camptothecin was administered to HESCs and in an OE mouse model.Main outcome measure(s)ITPR1 expression in OE lesions and normal endometrium, cell proliferation and apoptosis of HESCs with ITPR1 knockdown or camptothecin treatment, and autograft volume in the OE mouse model RESULT(S): Two significant OE-relevant gene modules were identified and involved the PI3K/Akt and aging-relevant pathways. Fifteen hub genes were identified and confirmed, among which the most significant gene, ITPR1, was robustly elevated in OE lesions. RNA sequencing revealed that ITPR1 was highly relevant to cell proliferation and apoptosis, which was further confirmed by CCK-8 assay, EdU staining, and flow cytometry analysis. ITPR1 knockdown inhibited cell proliferation and induced HESC apoptosis. The candidate drugs targeting these modules were screened, among which camptothecin and irinotecan were identified as promising drugs. Both compounds suppressed HESC proliferation and induced apoptosis; ITPR1 expression was suppressed by camptothecin. The therapeutic effect of camptothecin was also validated in the OE mouse model.Conclusion(s)This study identified the therapeutic targets and promising drugs for OE and shed light on the use of camptothecin in OE treatment.

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Condition tags

endometriosis

MeSH descriptors

Drug Discovery Endometriosis Inositol 1,4,5-Trisphosphate Receptors Ovarian Diseases Adult Animals Camptothecin Camptothecin Disease Models, Animal Endometriosis Endometrium Endometrium Female Humans Inositol 1,4,5-Trisphosphate Receptors Inositol 1,4,5-Trisphosphate Receptors Mice Mice, Inbred C57BL Middle Aged Ovarian Diseases

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