Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine and cocoa-based products are the main dietary sources of flavonoids. Flavonoids have been shown to possess a wide variety of anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis, autophagy, and suppress cancer cell proliferation and invasiveness. Flavonoids have dual action regarding ROS homeostasis—they act as antioxidants under normal conditions and are potent pro-oxidants in cancer cells triggering the apoptotic pathways and downregulating pro-inflammatory signaling pathways. This article reviews the biochemical properties and bioavailability of flavonoids, their anticancer activity and its mechanisms of action.

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Flavonoids as Anticancer Agents

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

https://www.mdpi.com/2072-6694/11/1/28/pdf

Flavonoids in Cancer and Apoptosis.

Cancer is the second leading cause of death worldwide. Conventional cancer therapies cause serious side effects and, at best, merely extend the patient's lifespan by a few years. Cancer control may therefore benefit from the potential that resides in alternative therapies. The demand to utilize alternative concepts or approaches to the treatment of cancer is therefore escalating. There is compelling evidence from epidemiological and experimental studies that highlight the importance of compounds derived from plants "phytochemicals" to reduce the risk of colon cancer and inhibit the development and spread of tumors in experimental animals. More than 25% of drugs used during the last 20 years are directly derived from plants, while the other 25% are chemically altered natural products. Still, only 5-15% of the approximately 250,000 higher plants have ever been investigated for bioactive compounds. The advantage of using such compounds for cancer treatment is their relatively non-toxic nature and availability in an ingestive form. An ideal phytochemical is one that possesses anti-tumor properties with minimal toxicity and has a defined mechanism of action. As compounds that target specific signaling pathways are identified, researchers can envisage novel therapeutic approaches as well as a better understanding of the pathways involved in disease progression. Here, we focus on 4 classes of natural anticancer drugs: methyltransferase inhibitors, DNA damaging/pro-oxidant drugs, HDAC inhibitors (HDACi), and mitotic disrupters, and we will focus on the mode of action for one promising example per group.

Overview of major classes of plant-derived anticancer drugs

Reactive oxygen species (ROS) promote carcinogenesis by inducing genetic mutations, activating oncogenes, and raising oxidative stress, which all influence cell proliferation, survival, and apoptosis. Cancer cells display redox imbalance due to increased ROS level compared to normal cells. This unique feature in cancer cells may, therefore, be exploited for targeted therapy. Over the past few decades, natural compounds have attracted attention as potential cancer therapies because of their ability to maintain cellular redox homeostasis with minimal toxicity. Preclinical studies show that bioactive dietary polyphenols exert antitumor effects by inducing ROS-mediated cytotoxicity in cancer cells. These bioactive compounds also regulate cell proliferation, survival, and apoptotic and antiapoptotic signalling pathways. In this review, we discuss (i) how ROS is generated and (ii) regulated and (iii) the cell signalling pathways affected by ROS. We also discuss (iv) the various dietary phytochemicals that have been implicated to have cancer therapeutic effects through their ROS-related functions.

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ROS-Mediated Cancer Cell Killing through Dietary Phytochemicals.

Citrus-derived flavonoids play important roles in the regulation of physiological conditions of citrus plants, including color changes of flower and fruit, flavor development, and anti-stress physiology. Moreover, citrus flavonoids possess multiple health-promoting effects in humans, and they are important ingredients for nutraceuticals and functional foods. The biosynthesis of flavonoids in citrus plants is of special significance because it determines the chemical structures and bioaccumulation of these bioactive compounds in the plants, which consequently influences their physiological functions in both citrus plants and human body. This review systematically summarizes: 1) the biosynthesis pathway of citrus-derived flavonoids, 2) the biosynthesis location and distribution of flavonoids in citrus plants, 3) the factors affecting flavonoid biosynthesis, 4) the biological significance of flavonoid biosynthesis in citrus plants, and 5) the health-promoting properties of citrus-derived flavonoids. The collation of this information provides scientific guidance for the development of healthy citrus foods and other health-promoting products containing citrus flavonoids.

Biosynthesis of citrus flavonoids and their health effects.

A natural predominant flavanone naringenin, especially abundant in citrus fruits, has a wide range of pharmacological activities. The search for antiproliferative agents that reduce skin carcinoma is a task of great importance. The objective of this study was to analyze the anti-proliferative and apoptotic mechanism of naringenin using MTT assay, DNA fragmentation, nuclear condensation, change in mitochondrial membrane potential, cell cycle kinetics and caspase-3 as biomarkers and to investigate the ability to induce reactive oxygen species (ROS) initiating apoptotic cascade in human epidermoid carcinoma A431 cells. Results showed that naringenin exposure significantly reduced the cell viability of A431 cells (p<0.01) with a concomitant increase in nuclear condensation and DNA fragmentation in a dose dependent manner. The intracellular ROS generation assay showed statistically significant (p<0.001) dose-related increment in ROS production for naringenin. It also caused naringenin-mediated epidermoid carcinoma apoptosis by inducing mitochondrial depolarization. Cell cycle study showed that naringenin induced cell cycle arrest in G0/G1 phase of cell cycle and caspase-3 analysis revealed a dose dependent increment in caspase-3 activity which led to cell apoptosis. This study confirms the efficacy of naringenin that lead to cell death in epidermoid carcinoma cells via inducing ROS generation, mitochondrial depolarization, nuclear condensation, DNA fragmentation, cell cycle arrest in G0/G1 phase and caspase-3 activation.

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Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest.

Piperine is a nitrogenous pungent substance exhibiting multifunctional pharmacological properties. However, the mechanism underlying its anticancer potential is not well elucidated in human oral sq...

Sultan Ahamad

Papers

Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest.

Piperine Triggers Apoptosis of Human Oral Squamous Carcinoma Through Cell Cycle Arrest and Mitochondrial Oxidative Stress.