Natural Flavonoids Quercetin and Kaempferol Targeting G2/M Cell Cycle-Related Genes and Synergize with Smac Mimetic LCL-161 to Induce Necroptosis in Cholangiocarcinoma Cells

Abstract

Cholangiocarcinoma (CCA) is an aggressive cancer associated with a very poor prognosis and low survival rates, primarily due to late-stage diagnosis and low response rates to conventional chemotherapy. Therefore, there is an urgent need to identify effective therapeutic strategies that can improve patient outcomes. Flavonoids, such as quercetin and kaempferol, are naturally occurring compounds that have attracted significant attention for their potential in cancer therapy by targeting multiple genes. In this study, we employed network pharmacology and bioinformatic analysis to identify potential targets of quercetin and kaempferol. The results revealed that the target genes of these flavonoids were enriched in G2/M-related genes, and higher expression of G2/M signature genes was significantly associated with shorter survival in CCA patients. Furthermore, in vitro experiments using CCA cells demonstrated that quercetin or kaempferol induced cell-cycle arrest in the G2/M phase. Additionally, when combined with a Smac mimetic LCL-161, an IAP antagonist, quercetin or kaempferol synergistically induced RIPK1/RIPK3/MLKL-mediated necroptosis in CCA cells while sparing non-tumor cholangiocyte cells. These findings shed light on an innovative therapeutic combination of flavonoids, particularly quercetin and kaempferol, with Smac mimetics, suggesting great promise as a necroptosis-based approach for treating CCA and potentially other types of cancer.

Antioxidant Activity of Quercetin-Containing Liposomes-in-Gel and Its Effect on Prevention and Treatment of Cutaneous Eczema

“…After the volatilization of alcohol, quercetin dissolved in it will precipitate and is not suitable for clinical use. In recent years, the anti-tumor, antioxidant, and anti-inflammatory effects of quercetin have been increasingly recognized [ 41 ]. Many quercetin dosage forms have been studied.…”

Selected Flavonols Targeting Cell Death Pathways in Cancer Therapy: The Latest Achievements in Research on Apoptosis, Autophagy, Necroptosis, Pyroptosis, Ferroptosis, and Cuproptosis

“…Utilization of inhibitors targeting pivotal necroptotic proteins, such as necrostatin-1 (Nec-1), GSK’872 (GSK), and necrosulfamide (NSA), which specifically inhibit RIPK1, RIPK3, and MLKL, respectively, revealed that all inhibitors markedly attenuated cell death provoked by the combination treatment of QUE and the Smac mimetic LCL-161 in cells. These studies indicate the involvement of the RIPK1/RIPK3/MLKL necroptosis pathway after treatment in cholangiocarcinoma cells [ 145 ].…”

“…The results following inhibitors targeting key necroptotic proteins also showed that all inhibitors significantly inhibited cell death induced by combined treatment of KEM with the Smac mimetic LCL-161 in cells. It is concluded that KEM, like QUE, influences the induction of necroptosis via the RIPK1/RIPK3/MLKL pathway [ 145 ].…”

Kaempferol inhibits the proliferation and migration of Epstein-Barr virus-positive diffuse large B-cell lymphoma cells

“…To enhance therapy, new therapeutic agents need to be developed to improve the cure rate of DLBCL. Kaempferol is a natural flavonoid with multiple pharmacological activities, including anticancer, anti-inflammatory, and anti-apoptotic effects [5]. Kaempferol has good antibacterial activity, and also has an effect on methicillin-resistant Staphylococcus aureus (MRSA) [6].…”

“…There is evidence that PI3K/Akt is vital in EBVinduced malignancies. The major EBV oncoprotein latent membrane protein (LMP) 1 and LMP2A activate PI3K/Akt axis, thereby affecting cell survival, apoptosis, and genomic instability [5]. Its downstream target protein is also known to cause cancer, and its role in DLBCL has also been demonstrated.…”