Premium
Tamoxifen enhances chemotherapeutic efficacy of C6‐ ceramide and increases induction of apoptosis in human colorectal cancer cells by upregulation of MAPK signaling pathway and down‐regulation of inhibitor of apoptosis protein, survivin
Author(s) -
Morad Samy,
Madigan James,
Rosenberg Daniel W,
Kester Mark,
Shanmugavelandy Sriram S,
Cabot Myles C
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.993.1
Subject(s) - survivin , ceramide , downregulation and upregulation , cancer research , apoptosis , inhibitor of apoptosis , tamoxifen , programmed cell death , chemistry , cancer , biology , medicine , breast cancer , biochemistry , gene
Resistance to chemotherapy is a critical barrier to successful treatment of colorectal cancer (CRC). Ceramide, because of its role in induction of cell death cascades in cancer cells, could be a functional therapeutic alternative. Previously we showed that P‐gp antagonists verapamil, tamoxifen, and cyclosporin A block ceramide glycosylation and synergistically enhance C6‐ceramide cytotoxicity in CRC cells; however, the mechanism underlying this response was unclear. Using tamoxifen as adjuvant to C6‐ ceramide, we show the combination is highly effective in CRC cell lines. In LoVo cells, the mix induced caspase‐dependent apoptosis (DNA fragmentation, PARP cleavage, caspase activation) dosedependently, and cell cycle arrest at both G1 and G2. At the molecular level, C6‐ceramide/tamoxifen elicited early upregulation of c‐Jun N‐terminal kinase, and induced upregulation of p53 tumor suppressor protein and downregulation of survivin. Kinetic evaluation indicated that JNK was upstream of both p53 and survivin. Research during the last decade has shown that JNK, p53, and survivin are important players in resistance to chemotherapy. Here we show for the first time, the versatile, composite effects of a new drug duo that could be an effective therapy for chemoresistant CRC and possibly other cancers, solid and hematological. Supported by NIH GM77391.