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.
Highlights
G-quadruplex (G4) structures are considered a promising therapeutic target in cancer
The progressive addition of Piperine analog-2 (PIP-2) and PIP-4 analogs cause an increase in the intensity of the negative peak for c-myc DNA in a dose-dependent manner (Fig. 6b,d).These findings indicate that Piperine analogs PIP-2 and PIP-4 interact with the c-myc G4 DNA structure and stabilize the parallel conformation of c-myc G4 DNA without disrupting its DNA structure, and the aromatic groups of these analogs can interact with the c-myc DNA bases via stacking mode[124,125]
We found that the Piperine analogs interact with the c-myc G4 DNA through stacking or the groove mode of interaction
Summary
G-quadruplex (G4) structures are considered a promising therapeutic target in cancer. 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. The NMR-based structural data of c-myc has shown that these G-rich sequences form polymorphic structures in potassium salt, and its major components are arranged in 1:2:1 loop form[41,44] This G-quadruplex motif, when stabilized by various G4 specific ligands, plays a crucial role in the downregulation of c-myc protein. Since c-myc is reported to be highly overexpressed in a large number of cancers, specific drugs promoting the G4 formation at the promoter site of this oncogene may reinforce anti-cancer activity by accomplishing multi-target m ethods[45,46]
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