Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways

Abstract

Cancer therapy is a growing field, and annually, a high number of research is performed to develop novel antitumor drugs. Attempts to find new antitumor drugs continue, since cancer cells are able to acquire resistance to conventional drugs. Natural chemicals can be considered as promising candidates in the field of cancer therapy due to their multiple-targeting capability. The nobiletin (NOB) is a ubiquitous flavone isolated from Citrus fruits. The NOB has a variety of pharmacological activities, such as antidiabetes, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective. Among them, the antitumor activity of NOB has been under attention over recent years. In this review, we comprehensively describe the efficacy of NOB in cancer therapy. NOB induces apoptosis and cell cycle arrest in cancer cells. It can suppress migration and invasion of cancer cells via the inhibition of epithelial-to-mesenchymal transition (EMT) and EMT-related factors such as TGF-β, ZEB, Slug, and Snail. Besides, NOB inhibits oncogene factors such as STAT3, NF-κB, Akt, PI3K, Wnt, and so on. Noteworthy, onco-suppressor factors such as microRNA-7 and -200b undergo upregulation by NOB in cancer therapy. These onco-suppressor and oncogene pathways and mechanisms are discussed in this review.

Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma

“…It is also noteworthy that some natural compounds have been widely used in clinics, such as paclitaxel 50 . Nobiletin, as a natural extract, can be considered as a promising candidate for cancer therapy due to its multiple-targeting capabilities 11 , 51 . But the underlying mechanisms and bioavailability of nobiletin are still complex problems to understand 11 , 51 , 52 , which limits its application as a therapeutic agent.…”

“…Nobiletin, as a natural extract, can be considered as a promising candidate for cancer therapy due to its multiple-targeting capabilities 11 , 51 . But the underlying mechanisms and bioavailability of nobiletin are still complex problems to understand 11 , 51 , 52 , which limits its application as a therapeutic agent. Our study demonstrated that nobiletin inhibited tumor progression by regulating the SKP2-p21/p27-CDK2-RB axis (working model, Figure 8F ): SKP2 targets p27 for degradation, CDK2 can be reactivated upon p27 degradation, and phosphorylation of RB is recovered by activated CDK2, which leads to G1/S transition, tumor growth, and progression.…”

Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals

“…Nobiletin (5,6,7,8,3’,4’-hexamethoxyflavone) is a polymethoxylated flavone found primarily in citrus fruits [ 153 ]. Nobiletin has been reported to exhibit several biological effects, including antioxidant, anti-inflammatory, anti-obesity, and anticancer properties [ 154 ]. In a colon cancer model induced by AOM-dextran sulfate sodium (DSS) in CD-1 mice, dietary intake of 0.05% nobiletin was reported to increase the protein levels of Nrf2 and increase the translocation to the nucleus [ 155 ].…”

Snail-Family Proteins: Role in Carcinogenesis and Prospects for Antitumor Therapy

“…Схожая активность описана для нобилетина -флавоноида из цитрусовых растений. Это соединение влияет на сигнальные пути TGF-β, ZEB, Slug и Snail, оно способно подавлять инвазию и миграцию опухолевых клеток [127]. Интерес исследователей к потенциальным ингибиторам ЭМП природного происхождения подкреплен относительно низкой токсичностью этих соединений для неопухолевых тканей, а также антиканцерогенными свойствами [128][129][130].…”