Transcriptional reprogramming contributes to the progression and recurrence of cancer. However, the poorly elucidated mechanisms of transcriptional reprogramming in tumors make the development of effective drugs difficult, and gene expression signature is helpful for connecting genetic information and pharmacologic treatment. So far, there are two gene-expression signature-based high-throughput drug discovery approaches: L1000, which measures the mRNA transcript abundance of 978 “landmark” genes, and high-throughput sequencing-based high-throughput screening (HTS2); they are suitable for anticancer drug discovery by targeting transcriptional reprogramming. L1000 uses ligation-mediated amplification and hybridization to Luminex beads and highlights gene expression changes by detecting bead colors and fluorescence intensity of phycoerythrin signal. HTS2 takes advantage of RNA-mediated oligonucleotide annealing, selection, and ligation, high throughput sequencing, to quantify gene expression changes by directly measuring gene sequences. This article summarizes technological principles and applications of L1000 and HTS2, and discusses their advantages and limitations in anticancer drug discovery.
Alzheimer's disease (AD) is the most common cause of dementia. Its pathology often accompanies inflammatory action, and astrocytes play important roles in such procedure. Rela(p65) is one of significant message factors in NF-κB pathway which has been reported high expression in astrocyte treated by Aβ. HupA, an alkaloid isolated from Chinese herb Huperzia serrata, has been widely used to treat AD and observations reflected that it improves memory and cognitive capacity of AD patients. To reveal its molecular mechanisms on p65, we cultured astrocytes, built Aβ-induced AD model, treated astrocytes with HupA at different concentrations, assayed cell viability with MTT, and detected p65 expression by immunohistochemistry and PCR. Our results revealed that treatment with 10 μM Aβ1-42 for 24 h induced a significant increase of NF-κB in astrocytes; HupA significantly down-regulated p65 expression induced by Aβ in astrocytes. This study infers that HupA can regulate NF-κB pathway to treat AD.
The purpose of the present study was to investigate the effect of bufadienolides on the a-375 melanoma cell line, and to delineate the underlying mechanism. a cell counting Kit-8 assay was used to determine the viability of the cells, and flow cytometry was used to evaluate apoptosis. Western blot analysis was used to evaluate the expression levels of proteins involved in the aKT pathway that are associated with apoptosis and autophagy. The results demonstrated that bufadienolides reduced the viability of a-375 cells in a dose-and a time-dependent manner. Following treatment with bufadienolides, a-375 cells exhibited clear properties that were characteristic of apoptosis and autophagy. The expression levels of the pro-apoptotic proteins Bax and p53 were upregulated, whereas those of the anti-apoptotic proteins, Bcl-2 and caspase-3 were downregulated. in addition, the level of a protein known to be associated with autophagy, microtubule-associated proteins 1a/1B light chain 3-ii, was increased, whereas that of p62 protein was reduced. Finally, the aKT signaling pathway was blocked in the bufadienolide-treated a-375 cells. in conclusion, these results revealed that bufadienolides effectively induced apoptosis and autophagy in a-375 cells via the aKT pathway, and therefore may be one of the candidate targets for the future development of targeted drugs to treat melanoma.
Signal transducer and activator of transcription 3 (STAT3) is known to be activated in numerous cancer types, including more than 40% of breast cancers. STAT3 ’s downstream gene cMyc serves as an important target in cancer treatment. However, the clinical availability of small-molecule inhibitors that can target cMyc are lacking.Cinnamic aldehyde (CA) has been reported to inhibit the proliferation of a variety of cancer cells, including those in breast cancer; however, its molecular mechanism remains unclear. This study examined CA induction of apoptosis in breast cancer cells via STAT3/cMyc pathway. The corresponding findings demonstrated that CA significantly inhibited the proliferation and migration of MDA-MB-231 cells, MCF-7 cells, and 4T1 cells in both a time and concentration-dependent manner. CA was also shown to enhance the effect of cMyc inhibitor 10074-G5 and was observed to be better than 10074-G5 in the same concentration. CA also inhibited the proliferation and migration of breast cancer cells, which may be related to the induction of breast cancer cells’ mitochondral apoptosis through the down-regulation of apoptosis-related proteins via STAT3/cMyc pathway. Accordingly, this study suggests that CA may serve as a novel cMyc inhibitor in breast cancer cells and should be further studied.
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