While considering the molecular pathogenesis of

While considering the molecular pathogenesis of an MPNST, the Ras/Raf/MEK/ERK, mTOR/AKT, p53, and PTEN pathways associated with tumor growth have been described (McCubrey et al., 2012). The involvement of receptor tyrosine kinases such as EGFR and TAM receptor families, and its associated molecular cascades have also been reported (Johansson et al., 2014, Katz et al., 2009). Nevertheless, no active and effective target therapy is currently approved in the clinic for MPNST. In India and China, the turmeric is a widely used herbal medicine for the ailments such as gastric problems, infectious diseases, inflammatory condition and others (Gupta et al., 2013). Curcumin (diferuloylmethane) is the most extensively studied component of turmeric which constitutes 2%–5% of its dried roots. It has been demonstrated that curcumin can induce apoptosis in tumor xav by inhibiting NF-κB activation (Chiang et al., 2014). Also, curcumin can inhibit cell growth in sarcomas such as chondrosarcoma or osteosarcoma (Lee et al., 2012, Li et al., 2012). Although curcumin is believed to be the main active ingredient for the function of turmeric, recent studies have indicated that the curcumin-free turmeric is as effective as or even more effective than the curcumin-containing turmeric (Aggarwal et al., 2013). A novel curcuminoid, Calebin-A ([(E)-4-(4‑hydroxy‑3-methoxyphenyl)-2-oxobut-3-enyl] (E)-3-(4‑hydroxy‑3-methoxyphenyl)prop‑2-enoate) was isolated from Curcuma longa L. (Park and Kim, 2002), which possesses potent biological activities (Aggarwal et al., 2013). Calebin-A exhibited the neuronal protective activity against β-amyloid insults in PC12 and IMR-32 cells (Kim et al., 2001, Park and Kim, 2002). Furthermore, this compound can inhibit cell growth and induced apoptosis in drug-resistant human gastric cancer cells (Li et al., 2008). Herein, we examine whether Calebin-A can also inhibit the proliferation of MPNST from NF1 patients and explore its underlying molecular mechanisms.
Methods
Results
Discussion This is a pilot study to evaluate the inhibitory effect of Calebin-A on MPNST cell proliferation. In both in vitro cell line and in vivo xenograft mouse models, Calebin-A demonstrates its ability to suppress the proliferation of four MPNST cell lines. The immunoblotting showed a significant decrease in phosphorylated AKT, acetylated H3, survivin and hTERT, but partially in phosphorylated ERK1/2 (only in two cell lines). These findings suggest that Calebin-A can inhibit the mTOR/AKT pathway. Growing evidence has demonstrated that curcumin targets numerous cancer signaling pathways such as Ras, PI3K, ALT, mTOR/AKT etc. (Kasi et al., 2016). Calebin-A is one of the curcuminoids, and its anti-cancer and anti-inflammatory effects have been reported to be related to NF-κB, RANKL, and MAPK signaling pathways (Li et al., 2008, Tyagi et al., 2016, Tyagi et al., 2017). The study showed the mTOR/AKT molecular signaling pathway might play a role for the anti-proliferation activity of Calebin-A.
Conclusion In summary, the study confirmed the anti-MPNST potential of Calebin-A. The reduced expression of phosphorylated AKT and partially the phosphorylated ERK1/2 suggests that the pathways of mTOR/AKT and Ras/Raf/MEK/ERK can be the targets. Moreover, the reduced expression of the anti-apoptotic molecule, survivin, and the enzyme to enhance cell mitosis, hTERT could also partially explain the inhibitory effect of Calebin-A. The down-regulation was ascribed to the decreased activity of HAT which implicates the histone acetylation. The in vivo study replicates the in vitro findings to confirm the inhibitory effect of Calebin-A on MPNST proliferation.
Introduction In post-translational modification, histone proteins acetylation by histone acetyltransferases (HATs) is an essential regulatory mechanism in epigenetic mark system, which controls the structural organization and transcriptional status of chromatin. Furthermore, it also plays an important role in many fundamental biological processes, such as DNA replication and repair, genome stability, histone deposition and nutrient metabolism [1]. Many studies have showed that aberrant HATs activities have been associated with the pathogenesis of many diseases, such as cancers, neurological disorders, HIV infection and inflammatory, etc. [2], [3], and HATs have emerged as significant biomarkers for these diseases, and its inhibitors contribute to the chemotherapy as well as drug discovery of anti-cancer agents. As a result, reliable approaches for detecting activity of HATs and screening of its inhibitors are critical for biochemical research and clinical diagnostics.