title: Spectroscopic investigation of the interaction between G-quadruplex of KRAS promoter sequence and three isoquinoline alkaloids.
abstract: KRAS promoter can form G-quadruplex structure and regulate gene transcription. The drugs which can bind with G-quadruplex of KRAS promoter may be potential remedy for treatment of cancers associated with KRAS mutation. The interaction mechanism between the G-quadruplex of KRAS promoter and three isoquinoline alkaloids (jatrorrhizine, berberine and sanguinarine) has been investigated by UV-visible, fluorescence and circular dichroism spectroscopic methods. The results showed that the three alkaloids can form complexes with G-quadruplex KRAS promoter with the molecular ratio of 1:1, and the binding constants were (0.90±0.16)×106Lmol-1, (0.93±0.21)×106Lmol-1and (1.16±0.45)×106Lmol-1for jatrorrhizine, berberine and sanguinarine. The absorption spectra, KI quenching and fluorescence anisotropy and polarization studies suggested jatrorrhizine and berberine interacted with G-quadruplex by not only end-stacking binding mode but also grooves or loops binding mode, while sanguinarine by end-stacking binding mode. Sanguinarine was more beneficial to maintain the stability and parallel conformation of KRAS promoter G-quadruplex. MTT assay was performed to evaluate antiproliferation effects of the three isoquinoline alkaloids on SW620 cells, and the antiproliferation effects of the three alkaloids were sanguinarine > berberine > jatrorrhizine. All the three alkaloids can bind with KRAS promoter G-quadruplex, and sanguinarine had the better binding property and antiproliferation effects on SW620 cells. The results obtained are meaningful to explore potential reagents targeting the parallel G-quadruplex structure of KRAS promoter for gene theraphy of colorectal carcinomas.
authors: Medical Science & Research Center of Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, People's Republic of China.
authors: Li-Na
authors: LN
authors: Wen
authors: Analytical & Testing Center of Beijing Normal University, Beijing 100875, People's Republic of China. Electronic address: xiemx@bnu.edu.cn.
authors: Meng-Xia
authors: MX
authors: Xie
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002942:Circular Dichroism; D005454:Fluorescence Polarization; D054856:G-Quadruplexes; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism*; D011193:Potassium Iodide / Q000737:chemistry; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; C117307:KRAS protein, human; D011193:Potassium Iodide; D016283:Proto-Oncogene Proteins p21(ras); C039109:isoquinoline
keywords: Binding mode; Isoquinoline alkaloids; KRAS promoter quadruplex; Spectroscopy