Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling

Abstract

Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer. Graphical abstract

Xanthohumol Suppresses Endometrial Cancer Cell Proliferation via Promotion of Smurf1-mediated ACLY Ubiquitination and Degradation

“…XN has undergone extensive investigation as an anticancer agent, with studies reporting its ability to inhibit the proliferation of various cancers. These cancers include gastric cancer 32 , breast cancer 22 , lung cancer 21 , cholangiocarcinoma 33 and colon cancer 23 . Furthermore, our previous experiments revealed that XN impeded cell proliferation by inducing paraptosis in leukemia cells 34 .…”

“…Xanthohumol (XN), a pentenyl avonoid extracted from hops, possesses anticancer, antioxidant, antibacterial, and anti-in ammatory activities 20 . Research has demonstrated that XN can impede the growth of various cancer types, such as lung cancer 21 , breast cancer 22 , colon cancer 23 , prostate cancer 24 , liver cancer 25 , and other cancers. This inhibition effect could be achieved by suppressing tumor cell proliferation, invasion, and migration, causing cell cycle arrest and inducing apoptosis.…”

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol

“…In addition, other study data provide evidence that the phytopharmaceutical stimulates autophagy in cancer cells through Beclin-1-independent pathways, including the modulation of Wnt/β-catenin signaling and direct inhibition of the mTOR-Unc-51-like kinase 1 pathway via ATP competition, indicating its multitarget mode of action and the importance of autophagy [ 56 , 169 ] ( Figure 7 ). Additionally, the mechanism of enhanced exocytosis was shown to be associated with resistance to therapy in conjunction with up-regulated NF-κB signaling, leading to the overexpression of chemoresistance proteins such as multidrug resistance protein (MDR1) and multidrug resistance-linked protein 1 (MRP1) in BC [ 170 ]. In this regard, resveratrol has been demonstrated to act as a chemosensitizer by modulating the expression of MDR1 and MRP1 in multidrug-resistant BC cells [ 171 ].…”

Orientin Promotes Antioxidant Capacity, Mitochondrial Biogenesis, and Fiber Transformation in Skeletal Muscles through the AMPK Pathway

“…Orientin, a member of the apigenin-8- C -glucoside family, is a flavonoid widespread in various edible plants. − It is a biologically active compound with multiple properties, making it the focus of interest in numerous studies. Orientin inhibits oxidative stress-induced endoplasmic reticulum stress and mitochondrial dysfunction via the AMPK pathway. − However, the potential of orientin to facilitate skeletal-muscle-fiber-type transformation remains unexplored.…”