3-methylquercetin and Colorectal-Neoplasms

Isorhamnetin, a flavonoid isolated from the fruits of herbal medicinal plants, such as Hippophae rhamnoides L., exerts anticancer effects similar to other flavonoids. However, the effect of isorhamnetin on colorectal cancer (CRC) and the underlying molecular mechanism are unclear. This study aimed to determine the effect of isorhamnetin on the proliferation of cells from the human CRC cell lines, HT‑29, HCT116 and SW480. It was demonstrated that isorhamnetin suppressed the proliferation of cells from all three cell lines, induced cell cycle arrest at the G2/M phase and suppressed cell proliferation by inhibiting the PI3K‑Akt‑mTOR pathway. Isorhamnetin also reduced the phosphorylation levels of Akt (ser473), phosph‑p70S6 kinase and phosph‑4E‑BP1 (t37/46) protein, and enhanced the expression of Cyclin B1 protein. Therefore, this compound was revealed to be a selective PI3K‑Akt‑mTOR pathway inhibitor, and may be a potent anticancer agent for the treatment of CRC, as it restrains the proliferation of CRC cells.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin B1; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Hippophae; HT29 Cells; Humans; M Phase Cell Cycle Checkpoints; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Quercetin; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases

Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and β-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and β-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression.

Topics: Animals; Apoptosis; Azoxymethane; beta Catenin; Blotting, Western; Cell Nucleus; Cell Proliferation; Colorectal Neoplasms; CSK Tyrosine-Protein Kinase; Dextran Sulfate; Humans; Immunoenzyme Techniques; Male; Mice; Phytotherapy; Plant Extracts; Protein Transport; Quercetin; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; src-Family Kinases; Tumor Cells, Cultured