Luteolin impacts deoxyribonucleic acid repair by modulating the mitogen-activated protein kinase pathway in colorectal cancer

Abstract

This study aimed to investigate the effects of luteolin on colorectal cancer (CRC) and explore its underlying mechanism. HCT-116 and HT-29 cells were treated with luteolin, cisplatin, or selumetinib. The cell survival, cell proliferation, apoptosis and cell cycle distribution, and DNA damage were detected using Cell Counting Kit-8, colony formation, flow cytometry, and immunofluorescence staining analysis, respectively. Western blotting was used to detect the expression of apoptosis-related, cycle-related, DNA-damage-related, and mitogen-activated protein kinase (MAPK) pathway-related proteins. Luteolin showed inhibitory effects on cellular growth by reducing cell survival and proliferation, inducing apoptosis and DNA damage, and arresting the cell cycle in a concentration-dependent manner in HCT-116 and HT-29 cells. Meanwhile, luteolin increased the expression of pro-apoptotic proteins, p-CHK1 (central to the induction of cell cycle arrest), and DNA excision repair protein and decreased anti-apoptotic proteins, G2-M phase-related proteins, and DNA repair proteins. The combination of cisplatin and luteolin significantly decreased cell survival and increased the apoptosis rate of HCT-116 and HT-29 cells compared with cisplatin alone. Bioinformatic analysis using the Comparative Toxicogenomics Database and STITCH and MalaCards databases showed that the MAPK pathway is involved in the pharmacology of luteolin. Furthermore, western blotting demonstrated that luteolin plays an inhibitory role by suppressing the MAPK signaling pathway in CRC, which is enhanced when combined with selumetinib. Luteolin can also prevent tumourigenesis in CRC in vivo. In conclusion, luteolin suppressed cell proliferation, blocked the cell cycle, and induced DNA damage and apoptosis progression in CRC cells by mediating the MAPK pathway

Identification of peanut skin components for treating hepatocellular carcinoma via network pharmacology and in vitro experiments

“…According to the network diagram, the main active compounds of PS that act on HCC are luteolin, quercetin, β‐sitosterol, pratensein, and chrysoeriol. Luteolin is a flavonoid that can be used as an antitumor agent to prevent tumor cell proliferation, avoid carcinogenic stimuli, activate cell cycle arrest, and induce cell apoptosis through different signal transduction pathways during in vivo and in vitro cancer development (Imran et al., 2019); therefore, luteolin can be a potential antitumor drug (Song et al., 2022). In hepatocytes, the combination of luteolin and 5‐fluorouracil can increase the ratio of BCL2‐associated X (bax)/B‐cell lymphoma‐2 (bcl‐2) and the expression of tumor protein p53 (TP53), enhance the cleavage of polyADP ribose polymerase (PARP), and reduce the content of dihydropyrimidine dehydrogenase (Verschooten et al., 2010).…”

Therapeutic Potential of Luteolin on Cancer

“…Further molecular mechanism studies showed that the Luteolin demonstrated an inhibitory effect on LoVo cells’ proliferation through inhibition of the cell cycle arrest at the G2/M phase transition, inactivating cyclin B1/cell division cycle 2 (CDC2), followed by the induction of apoptosis by cytochrome c- and deoxyadenosine triphosphate-mediated activation of apoptotic protease activating factor 1 [ 50 ]. In a study by Song et al, 2022, Luteolin was found to suppress cell proliferation, cause cell cycle arrest, and induce DNA damage and apoptosis in CRC cells through modulation of the MAPK pathway, while Luteolin inhibited the tumor growth in the CRC xenograft model in vivo [ 51 ]. Additionally, in the same study, Song et al 2022 demonstrated that Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells, as the combination of Luteolin and cisplatin caused a significant decrease in cell survival and increased the rate of apoptosis of HCT-116 and HT-29 cells, compared with the only cisplatin treatment [ 51 ].…”

“…In a study by Song et al, 2022, Luteolin was found to suppress cell proliferation, cause cell cycle arrest, and induce DNA damage and apoptosis in CRC cells through modulation of the MAPK pathway, while Luteolin inhibited the tumor growth in the CRC xenograft model in vivo [ 51 ]. Additionally, in the same study, Song et al 2022 demonstrated that Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells, as the combination of Luteolin and cisplatin caused a significant decrease in cell survival and increased the rate of apoptosis of HCT-116 and HT-29 cells, compared with the only cisplatin treatment [ 51 ].…”

Luteolin, a Potent Anticancer Compound: From Chemistry to Cellular Interactions and Synergetic Perspectives

“…Poor solubility of flavonoids has always been a daunting task for scientists, being widely researched to explore their hidden therapeutic mechanisms. As discussed above, luteolin is known to inhibit tumorigenesis in a diverse range of cancers by inhibiting the viability, migration, angiogenesis and invasion [ 11 , 12 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ]. However, the combination of protein and flavonoids can ameliorate the problems of poor solubility and stability of flavonoids for better utilization.…”