Abstract
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.
Highlights
IκBα must undergo phosphorylation, ubiquitination and degradation
The primers for cyclinD1, survivin, Bax, antisense non-coding RNA in the INK4 locus (ANRIL), lincRNA-Tnfaip[3], HOX transcript antisense RNA (HOTAIR), growth arrest specific 5 (GAS5), NKILA, H19 and GAPDH were purchased from Eurofins Genomics (Bangalore, Karnataka)
We examined the relative potency of IDET and DET in breast cancer cells (Fig. 1A)
Summary
IκBα must undergo phosphorylation, ubiquitination and degradation. The p65-p50 subunit is released and translocate from the cytoplasm to the nucleus. Some of the NF-κB associated lncRNAs include antisense non-coding RNA in the INK4 locus (ANRIL)[9], HOX transcript antisense RNA (HOTAIR)[10], Lethe[11], Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1)[12], NF-κB interacting lncRNAs (NKILA)[13] and H1914 Because of their crucial role during tumorigenesis, lncRNAs has been targeted therapeutically by the approaches such as antisense oligonucleotides and RNAi technology. Elephantopus scaber Linn (family Asteraceae) is a small herb mainly distributed in Africa, Asia, Australia and Europe[16] The extract from this plant has been shown to exhibit analgesic, anti-asthamatic, anti-diabetic, anti-inflammatory, anti-microbial, anti-oxidant, anti-platelet, hepatoprotective and wound healing activities[17]. Previous studies have demonstrated that IDET exhibit activities against some cancer types. The aim of this study was to examine the anticancer potential of IDET and DET in breast cancer cells. Whether IDET can modulate lncRNAs expression, generation of reactive oxygen species (ROS) and NF-κB activation was investigated
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