A multi-scale systems pharmacology approach uncovers the anti-cancer molecular mechanism of Ixabepilone
| Autor: | Shi-long Jiang, Yi-Di Guan, Jin-Ming Yang, Yi Zhang, Dong-Sheng Cao, Yan Cheng, Liu-Xia Zhang, Xi-Sha Chen, Alex F. Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Mice
Nude Antineoplastic Agents Apoptosis 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Breast cancer Drug Discovery medicine Tumor Cells Cultured Animals Humans 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Gene knockdown Mice Inbred BALB C Oncogene Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Autophagy Ixabepilone Cancer Mammary Neoplasms Experimental General Medicine medicine.disease 0104 chemical sciences Proto-Oncogene Proteins c-bcl-2 Tumor progression Epothilones Cancer research Female Drug Screening Assays Antitumor Systems pharmacology |
| Zdroj: | European journal of medicinal chemistry. 199 |
| ISSN: | 1768-3254 |
| Popis: | It has been realized that FDA approved drugs may have more molecular targets than is commonly thought. Thus, to find the exact drug-target interactions (DTIs) is of great significance for exploring the new molecular mechanism of drugs. Here, we developed a multi-scale system pharmacology (MSSP) method for the large-scale prediction of DTIs. We used MSSP to integrate drug-related and target-related data from multiple levels, the network structural data formed by known drug-target relationships for predicting likely unknown DTIs. Prediction results revealed that Ixabepilone, an epothilone B analog for treating breast cancer patients, may target Bcl-2, an oncogene that contributes to tumor progression and therapy resistance by inhibiting apoptosis. Furthermore, we demonstrated that Ixabepilone could bind with Bcl-2 and decrease its protein expression in breast cancer cells. The down-regulation of Bcl-2 by Ixabepilone is resulted from promoting its degradation by affecting p-Bcl-2. We further found that Ixabepilone could induce autophagy by releasing Beclin1 from Beclin1/Bcl-2 complex. Inhibition of autophagy by knockdown of Beclin1 or pharmacological inhibitor augmented apoptosis, thus enhancing the antitumor efficacy of Ixabepilone against breast cancer cells in vitro and in vivo. In addition, Ixabepilone also decreases Bcl-2 protein expression and induces cytoprotective autophagy in human hepatic carcinoma and glioma cells. In conclusion, this study not only provides a feasible and alternative way exploring new molecular mechanisms of drugs by combing computation DTI prediction, but also reveals an effective strategy to reinforce the antitumor efficacy of Ixabepilone. |
| Databáze: | OpenAIRE |
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