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G‐Quadruplex‐Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c‐MYC and BCL2 Expression
Author(s) -
Paul Rakesh,
Das Tania,
Debnath Manish,
Chauhan Ajay,
Dash Jyotirmayee
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900534
Subject(s) - gene knockdown , synthetic lethality , microbiology and biotechnology , small interfering rna , chemistry , transcription (linguistics) , biology , dna , promoter , cell cycle checkpoint , apoptosis , gene , luciferase , cancer cell , rna , gene expression , cell cycle , dna repair , biochemistry , transfection , cancer , genetics , linguistics , philosophy
Herein, a prolinamide‐derived peptidomimetic that preferentially binds to c‐MYC and BCL2 G‐quadruplexes present in the promoter regions of apoptosis‐related genes ( c‐MYC and BCL2 ) over other DNA quadruplexes are described. Biological assays, such as real‐time quantitative reverse transcription, western blot, dual luciferase, and small interfering RNA knockdown assays, indicate that the ligand triggers a synthetic lethal interaction by simultaneously inhibiting the expression of c‐MYC and BCL2 genes through their promoter G‐quadruplexes. The ligand shows antiproliferative activity in MCF‐7 cells that overexpress both MYC and BCL2 genes, in comparison to cells that overexpress either of the two. Moreover, the ligand induces S‐phase cell‐cycle arrest, DNA damage, and apoptosis in MCF‐7 cells.