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The specific 26S proteasome inhibitor, bortezomib (BZ) potently inducesapoptosis as well as autophagy in metastatic breast cancer cell lines such asMDA-MB-231 and MDA-MB-468. The combined treatment of clarithromycin (CAM) andBZ significantly enhances cytotoxicity in these cell lines. Although treatmentwith up to 100 µg/ml CAM alone had little effect on cell growth inhibition, theaccumulation of autophagosomes and p62 was observed after treatment with 25 µg/mlCAM. This result indicated that CAM blocked autophagy flux. However, the combinedtreatment of BZ and CAM resulted in more pronounced autophagy induction, as assessedby increased expression ratios of LC3B-II to LC3B-I and clearance of intracellularp62, than treatment with BZ alone. This combination further enhanced inductionof the pro-apoptotic transcription factor CHOP (CADD153) and the chaperone proteinGRP78. Knockdown of CHOP by siRNA attenuated the death-promoting effect of BZin MDA-MB-231 cells. A wild-type murine embryonic fibroblast (MEF) cell line alsoexhibited enhanced BZ-induced cytotoxicity with the addition of CAM, whereas aChop knockout MEF cell line completely abolished this enhancement and exhibitedresistance to BZ treatment. These data suggest that endoplasmic reticulum (ER)-stressmediated CHOP induction is involved in pronounced cytotoxicity by combining thesereagents. Simultaneously targeting two major intracellular protein degradationpathways such as the ubiquitin-proteasome system by BZ and the autophagy-lysosomepathway by CAM may improve the therapeutic outcome in breast cancer patients viaER-stress mediated apoptosis.

international journal of oncology

Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells