deoxyelephantopin and Breast-Neoplasms

The sesquiterpene lactones, Isodeoxyelephantopin (IDET) and Deoxyelephantopin (DET) are known to exhibit activities against some cancer types. The activities of these lactones against breast cancer and the molecular bases is not known. We examined the efficacy of lactones in breast cancer preclinical model. Although both lactones exhibited drug like properties, IDET was relatively effective in comparison to DET. IDET suppressed the proliferation of both invasive and non-invasive breast cancer cell lines. IDET also suppressed the colony formation and migration of breast cancer cells. The assays for Acridine Orange (AO)/Propidium Iodide (PI) staining, cell cycle distribution, phosphatidylserine externalization and DNA laddering suggested the apoptosis inducing potential of IDET. The treatment with IDET also induced an accumulation of cells in the sub-G1 and G2/M phases. The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP. The lactone induced reactive oxygen species (ROS) generation in breast cancer cells. Further, the use of N-acetyl cysteine (NAC) suppressed IDET induced ROS generation and apoptosis. The NF-κB-p65 nuclear translocation induced by okadaic acid (OA) was suppressed by the sesquiterpene. IDET also suppressed the expression of NF-κB regulated tumorigenic proteins, and induced the expression of proapoptotic gene (Bax) in cancer cells. While the expression of oncogenic lncRNAs was suppressed, the tumor suppressor lncRNAs were induced by the sesquiterpene. Collectively, the modulation of multiple cell signaling molecules by IDET may contribute to its activities in breast cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Asteraceae; Breast Neoplasms; Cell Proliferation; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Lactones; Membrane Potential, Mitochondrial; Reactive Oxygen Species; RNA, Long Noncoding; Sesquiterpenes; Signal Transduction; Stereoisomerism; Transcription Factor RelA

Elephantopus scaber L. (Asteraceae) is a traditional herbal medicine with anti-cancer effects. We evaluated the in vitro and in vivo efficacy of a major sesquiterpene lactone constituent of E. scaber, deoxyelephantopin (DET), against mammary adenocarcinoma and the underlying molecular mechanism.. A variety of cellular assays, immunoblotting and immunohistochemistry, as well as both orthotopic and metastatic TS/A tumour models in BALB/c mice, were used. Test mice were pretreated and post-treated with DET or paclitaxel and mammary tumour growth evaluated.. DET (< or =2 microg x mL(-1)) significantly inhibited colony formation, cell proliferation, migration and invasion of TS/A cells and induced G(2)/M arrest and apoptosis in TS/A cells. c-Jun N-terminal kinase-mediated p21(Waf1/Cip1) expression and caspase activation cascades were up-regulated by DET, effects suppressed by N-acetyl-L-cysteine. Moreover, tumour necrosis factor alpha-induced matrix metalloproteinase-9 enzyme activity and expression and nuclear factor-kappa B activation were abolished by DET. Pretreatment with DET was more effective than paclitaxel, for profound suppression of orthotopic tumour growth (99% vs. 68% reduction in tumour size) and lung metastasis of TS/A cells (82% vs. 63% reduction in metastatic pulmonary foci) and prolonged median survival time (56 vs. 37 days, P < 0.01) in mice. The levels of cyclooxygenase-2 and vascular endothelial growth factor in metastatic lung tissues of TS/A-bearing mice were attenuated by DET.. Our data provide evidence for the suppression of mammary adenocarcinoma by DET with several mechanisms and suggest that DET has potential as a chemopreventive agent for breast cancer.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Breast Neoplasms; Caspases; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 2; Dose-Response Relationship, Drug; Female; Humans; JNK Mitogen-Activated Protein Kinases; Lactones; Lung Neoplasms; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; NF-kappa B; Paclitaxel; Reactive Oxygen Species; Sesquiterpenes; Time Factors; Tumor Burden; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays