期刊
JOURNAL OF CELL SCIENCE
卷 122, 期 18, 页码 3330-3339出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.048181
关键词
LC3; Cell death; Anti-depressant; Doxorubicin; Chemotherapy; Atg5; p62 (SQSTM1)
类别
资金
- Medical Research Council
- Telethon AIRC
- EU [LSGBH-2005-019067-Epistem]
- Philip Morris USA Inc. [FIRB-RBNE01KJHT_ 004]
- MIUR
- MinSan
- ISS 'Program Italia-USA' [N526D5, ACC12]
- Italian Human ProteomeNet [RBRN07BMCT_ 007]
- MRC [MC_U132670600] Funding Source: UKRI
- Medical Research Council [MC_U132670600] Funding Source: researchfish
Alterations in the autophagic pathway are associated with the onset and progression of various diseases. However, despite the therapeutic potential for pharmacological modulators of autophagic flux, few such compounds have been characterised. Here we show that clomipramine, an FDA-approved drug long used for the treatment of psychiatric disorders, and its active metabolite desmethylclomipramine (DCMI) interfere with autophagic flux. Treating cells with DCMI caused a significant and specific increase in autophagosomal markers and a concomitant blockage of the degradation of autophagic cargo. This observation might be relevant in therapy in which malignant cells exploit autophagy to survive stress conditions, rendering them more susceptible to the action of cytotoxic agents. In accordance, DCMI-mediated obstruction of autophagic flux increased the cytotoxic effect of chemotherapeutic agents. Collectively, our studies describe a new function of DCMI that can be exploited for the treatment of pathological conditions in which manipulation of autophagic flux is thought to be beneficial.
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