Vitamin E analog, alpha-TEA, induces apoptosis in cisplatin sensitive and resistant human ovarian cancer cells and sensitizes resistant cells to cisplatin induced apoptosis: mechanistic study of signaling pathways
Weiping Yu, Kristen Anderson, Bob G. Sanders, Kimberly Kline. Univisity of Texas at Austin, Austin, TX and Tufts University, Boston, MA.
Cisplatin resistance is a major cause for treatment failure in ovarian cancer; 90% patients die with metastatic disease, highlighting the urgent need of more effective strategies for overcoming drug resistance either by direct killing of tumors or sensitizing the cancer cells to first line drug treatments.
alpha-TEA, an analog of RRR-alpha-tocopherol (RRR-alpha-tocopherol ether-linked acetic acid) induces both cisplatin (CDDP) sensitive A2780 and resistant A2780/cp70 human ovarian cancer cells to undergo apoptosis in a dose dependent manner; whereas, CDDP induces apoptosis only in the A2780 cells.
Treatment of A2780/cp70 cells with alpha-TEA + CDDP produces high levels of apoptosis significantly greater than separate treatments. Combination treatments with alpha-TEA + CDDP significantly reduced tumor burden, visible lung metastases, and microscopic lung metastases of A2780/cp70-GFP (green fluorescent protein) CDDP-resistant ovarian cancer cells transplanted into immunodeficient mice when compared to control or either treatment alone.
alpha-TEA-induced apoptosis in human ovarian cancer cells is mediated via restoration of pro-apoptotic Fas/ Fas-ligand signaling pathway, induction of increased intensity and prolonged activation of the pro-apoptotic MAPK c-Jun N-terminal kinase (JNK) and its down-stream target, c-Jun transcription factor, and suppression of constitutively activated pro-survival Akt and MAPK extracellular regulated kinase (ERK1/2).
These events trigger a caspase 8 and JNK-involved mitochondria-dependent apoptotic cascade; namely, Fas/FADD/caspase 8/Bid/Bax/cytochrome c/caspase 9/caspase 3/apoptosis and Fas/Daxx/JNK/Bax/cytochrome c/caspase 9/caspase 3/apoptosis, and a caspase 8-mediated mitochondria-independent apoptotic pathway; Fas/FADD/caspase 8/caspase 3/apoptosis.
We speculate that alpha-TEA-induced suppression of constitutively activated pro-survival Akt and MAPK extracellular regulated kinase (ERK1/2) may be one of the mechanisms whereby á-TEA sensitizes A2780/cp70 ovarian cancer cells to CDDP-induced apoptosis.
In summary, alpha-TEA is a potential therapeutic agent for CDDP sensitive ovarian cancer, and mediator to sensitize CDDP treatment for CDDP resistant ovarian cancer.
Supported by CA59730, ES07784, and the Foundation for Research.
AACR 2005 Abstract #5359
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