Chelerythrine chloride inhibits the progression of colorectal cancer by targeting cancer‐associated fibroblasts through intervention with WNT10B/β‐catenin and TGFβ2/Smad2/3 axis

Abstract

Chelerythrine chloride (CHE) is a benzodiazepine alkaloid derived from natural herbs with significant anti‐tumor and anti‐inflammatory activities. However, the exact role and underlying mechanisms of CHE in colorectal cancer (CRC) remain unclear. Therefore, this study is aimed to investigate the influence of CHE on the progression of CRC. Cell Counting Kit‐8 assay (CCK‐8), transwell, apoptosis rate, cell cycle distribution, reactive oxygen species (ROS), and colony formation determined the anti‐proliferative activity of CHE in CRC cell lines. Transcriptome sequencing and western blot were used to explore the mechanism. Finally, H&E staining, Ki67, TUNEL, and immunofluorescence were conducted to verify the anti‐CRC activity and potential mechanisms of CHE in vivo. CHE had a prominent inhibitory effect on the proliferation of CRC cells. CHE induces G1 and S phase arrest and induces cell apoptosis by ROS accumulation. Cancer‐associated fibroblasts (CAFs) play a key role in CRC metastasis. Then, this study found that CHE regulates WNT10B/β‐catenin and TGFβ2/Smad2/3 axis, thereby decreasing the expression of α‐SMA, which is a maker of CAFs. Taken together, CHE is a candidate drug and a potent compound for metastatic CRC, which can intervene CAFs in a dual pathway to effectively inhibit the invasion and migration of cancer cells, which can provide a new choice for future clinical treatment.

Chelerythrine induces apoptosis and ferroptosis through Nrf2 in ovarian cancer cells

“…endoplasmic reticulum stress and subsequent apoptosis [15]. Furthermore, research in zebrafish has unveiled that CHE's developmental toxicity hinges on its control of intracellular ROS levels, involving the inhibition of Nrf2 and the upregulation of recombinant Keap1, a specific target of Nrf2 [16].…”

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids

“…Moreover, the main mechanism of action is correlated with the alteration of phosphoinositide 3-kinase (PI3K), Akt, and the mammalian target of rapamycin (mTOR) signaling pathways [ 35 ]. Chelerythrine ( 2 ) has exhibited anticancer activity in vivo and in vitro, and considerable existing research has confirmed that chelerythrine can act on different pathways (e.g., DNA, MAPK, apoptosis, ROS, cell cycle, autophagy, tumor metastasis, and PKC) to inhibit or facilitate apoptosis in a variety of cancer cells (e.g., non-small cell lung cancer [ 36 ], prostate cancer [ 37 ], lung adenocarcinoma [ 38 ], renal cancer [ 39 ], and melanoma cells [ 40 ], colorectal cancer [ 41 ]), thus suggesting that the benzophenanthridine alkaloids exhibit high anticancer activity. Previous studies have proven that chelerythrine ( 2 ) exhibits antitumor stem cell properties, which are mediated by the downregulation of β- Catenin expression, thus inhibiting non-small cell lung cancer stem cells [ 42 ].…”

Effect of dietary supplementation with sanguinarine on meat quality and lipid metabolism of broilers

“…Which are not only similar in structure, but also similar in mechanism of action ( Liu et al, 2023 ). Both alkaloids have been proved to have antibacterial and anti-inflammatory activities, with the activity of sanguinarine being more prominent ( Hamoud et al, 2014 ; Kumar and Hazra, 2015 ; Xue et al, 2017 ; Kulíšková et al, 2023 ; Liang et al, 2023 ). Currently, the research on MCE is mainly focused on improving the growth performance of poultry, and there is no study on the mechanism of its regulation of meat quality.…”