![]() ![]() Additionally, in estrogen receptor α-negative breast cancer patients, therapeutic outcome for anthracycline-based chemotherapy is unsatisfactory ( 4). However, despite the significant benefits of tamoxifen treatment, almost all patients with metastatic disease and as many as 40% of the patients receiving adjuvant tamoxifen therapy do not respond, or acquire resistance during treatment ( 3). ![]() Blocking the action of estrogen receptor α by selective estrogen receptor modulators, such as tamoxifen, has been the most common treatment strategy for breast cancer patients ( 2). Simultaneously targeting two major intracellular protein degradation pathways such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome pathway by CAM may improve the therapeutic outcome in breast cancer patients via ER-stress mediated apoptosis.Īpproximately 75% of breast cancer is categorized as estrogen receptor α-positive, with estradiol-bound estrogen receptor α as the key determinant in promoting breast cancer growth ( 1). These data suggest that endoplasmic reticulum (ER)-stress mediated CHOP induction is involved in pronounced cytotoxicity by combining these reagents. A wild-type murine embryonic fibroblast (MEF) cell line also exhibited enhanced BZ-induced cytotoxicity with the addition of CAM, whereas a Chop knockout MEF cell line completely abolished this enhancement and exhibited resistance to BZ treatment. Knockdown of CHOP by siRNA attenuated the death-promoting effect of BZ in MDA-MB-231 cells. This combination further enhanced induction of the pro-apoptotic transcription factor CHOP (CADD153) and the chaperone protein GRP78. ![]() However, the combined treatment of BZ and CAM resulted in more pronounced autophagy induction, as assessed by increased expression ratios of LC3B-II to LC3B-I and clearance of intracellular p62, than treatment with BZ alone. This result indicated that CAM blocked autophagy flux. Although treatment with up to 100 μg/ml CAM alone had little effect on cell growth inhibition, the accumulation of autophagosomes and p62 was observed after treatment with 25 μg/ml CAM. The combined treatment of clarithromycin (CAM) and BZ significantly enhances cytotoxicity in these cell lines. The specific 26S proteasome inhibitor, bortezomib (BZ) potently induces apoptosis as well as autophagy in metastatic breast cancer cell lines such as MDA-MB-231 and MDA-MB-468. ![]()
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