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Piperine analogs arrest c-myc gene leading to downregulation of transcription for targeting cancer.

ABSTRACT: G-quadruplex (G4) structures are considered a promising therapeutic target in cancer. Since Ayurveda, Piperine has been known for its medicinal properties. Piperine shows anticancer properties by stabilizing the G4 motif present upstream of the c-myc gene. This gene belongs to a group of proto-oncogenes, and its aberrant transcription drives tumorigenesis. The transcriptional regulation of the c-myc gene is an interesting approach for anticancer drug design. The present study employed a chemical similarity approach to identify Piperine similar compounds and analyzed their interaction with cancer-associated G-quadruplex motifs. Among all Piperine analogs, PIP-2 exhibited strong selectivity, specificity, and affinity towards c-myc G4 DNA as elaborated through biophysical studies such as fluorescence emission, isothermal calorimetry, and circular dichroism. Moreover, our biophysical observations are supported by molecular dynamics analysis and cellular-based studies. Our study showed that PIP-2 showed higher toxicity against the A549 lung cancer cell line but lower toxicity towards normal HEK 293 cells, indicating increased efficacy of the drug at the cellular level. Biological evaluation assays such as TFP reporter assay, quantitative real-time PCR (qRT- PCR), and western blotting suggest that the Piperine analog-2 (PIP-2) stabilizes the G-quadruplex motif located at the promoter site of c-myc oncogene and downregulates its expression. In conclusion, Piperine analog PIP-2 may be used as anticancer therapeutics as it affects the c-myc oncogene expression via G-quadruplex mediated mechanism.

SUBMITTER: Pandya N

PROVIDER: S-EPMC8617303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is accumulating evidence showing that hyperglycemia conditions like diabetes possess a greater risk of impairment to the neuronal system because high glucose levels exacerbate oxidative stress, accumulation of amyloid-beta peptides, and mitochondrial dysfunction, and impair cognitive functions and cause neurodegeneration conditions like Alzheimer's diseases. Due to the extensive focus on pharmacological intervention to prevent neuronal cells' impairment induced by hyperglycemia, the underlying molecular mechanism that links between Diabetes and Alzheimer's is still lacking. Given this, the present study aimed to evaluate the protective effect of piperine on streptozotocin (STZ) induced hyperglycemia and candidate gene expression. In the present study, rats were divided into four groups: control (Vehicle only), diabetic control (STZ only), piperine treated (20 mg/kg day, i.p), and sitagliptin (Positive control) treated. The memory function was assessed by Morris water maze and probe test. After treatment, biochemical parameters such as HOMA index and lipid profile were estimated in the serum, whereas histopathology was evaluated in pancreatic and brain tissue samples. Gene expression studies were done by real-time PCR technique. Present data indicated that piperine caused significant memory improvement as compared to diabetic (STZ) control. The assessment of HOMA indices in serum samples showed that piperine and sitagliptin (positive control, PC) caused significant alterations of insulin resistance, β cell function, and insulin sensitivity. Assessment of brain and pancreas histopathology shows significant improvement in tissue architecture in piperine and sitagliptin treated groups compared to diabetic control. The gene expression profile in brain tissue shows significantly reduced BACE1, PSEN1, APAF1, CASPASE3, and CATALASE genes in the piperine and sitagliptin (PC) treated groups compared to Diabetic (STZ) control. The present study demonstrated that piperine not only improves memory in diabetic rats but also reduces the expression of specific AD-related genes that can help design a novel strategy for therapeutic intervention at the molecular level.

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Piperine analogs arrest c-myc gene leading to downregulation of transcription for targeting cancer.

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