Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells.
Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-alpha (ER-alpha)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-alpha status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-alpha-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-alpha status.
Lagadec
C
C
INSERM ERI-8 (JE2488), Growth Factor Signaling in Breast Cancer, Functional Proteomics, IFR147, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.
Adriaenssens
E
E
Toillon
R A
RA
Chopin
V
V
Romon
R
R
Van Coppenolle
F
F
Hondermarck
H
H
Le Bourhis
X
X
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006131:Growth Inhibitors / Q000627:therapeutic use; D006801:Humans; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology* / Q000627:therapeutic use; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D006131:Growth Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D013629:Tamoxifen