Quercetin and Ursolic Acid: Dietary Moieties with Promising Role in Tumor Cell Cycle Arrest

Review Article

Austin Oncol. 2016; 1(2): 1010.

Quercetin and Ursolic Acid: Dietary Moieties with Promising Role in Tumor Cell Cycle Arrest

Kashyap D¹, Sharma A², Mukherjee TK³, Tuli HS³* and Sak K4

¹Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, India

²Department of Chemistry, Career Point University, Tikker-kharwarian, Hamirpur, Himachal Pradesh, India

³Department of Biotechnology, M.M. University, Mulana, Ambala, Haryana, India

4Department of Hematology and Oncology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia

*Corresponding author: Hardeep Singh Tuli, Assistant Professor, Department of Biotechnology, M.M University, Mullana-Ambala, Haryana, India

Received: September 05, 2016; Accepted: October 05, 2016; Published: October 07, 2016


Despite extensive efforts done in the recent decades, cancer has still remained an incurable disorder. On the other hand, there is no doubt that different natural compounds possess a huge potential to suppress the promotion and progression of tumorigenesis, and numerous studies have described the possible molecular mechanisms of such substances. Probably one of the most efficient ways to hinder the multiplication of cancer cells is to arrest their cell cycle progression. Therefore, in the current article, a detailed review is presented about the arrest of cell cycle in different phases followed by exposure of cancer cells to two natural dietary agents, quercetin, and ursolic acid. Both these compounds have previously been shown to exert anticancer properties, whereas pleiotropic action mechanisms were proposed. The current work describes a variety of molecules occupied in regulation of cell cycle progression and transition between different phases initiated by treatment of cancer cells with the respective flavonoid and triterpenoid. It is clear that better knowledge about the processes and molecules involved in cell cycle, as well as possibilities to modulate such mechanisms by natural compounds, may lead to the development of more efficient and targeted chemopreventive and chemotherapeutic strategies in the future.

Keywords: Cancer treatment and prevention; Cell cycle arrest; Natural dietary agents; Quercetin; Ursolic acid


Studies in last few decades utilizing phytochemicals have ameliorated and emerged as an incipient platform for cancer treatment [1-3]. Several phytochemicals with anti-cancer properties have superseded the synthetic chemotherapeutic molecules due to lesser side effects [4]. Among the variety of health benign phytochemicals, quercetin (Quer, flavonoid) and ursolic acid (UA, triterpenoid) are emerging as promising therapeutics [5-15]. Being pharmacologically active, these phytochemicals are intensively utilized in chemoprevention and treatment. UA and Quer are kenned to modulate the sundry anti-cancer cell signaling pathways, such as induction of apoptosis, anti-angiogenesis, anti-metastasis, and cell cycle inhibition [16-20]. Especially in the cell cycle, a variety of different transcriptional factors and regulatory proteins are kenned to play a paramount role that is being targeted for cancer treatment and prevention.

In most eukaryotes, cell cycle-regulated transcription can be grouped into three main waves that coincide with the different transition points during the cell cycle, namely G1-to-S, G2-to-M and M-to-G1 [21,22]. Following mitotic division, a somatic cell undergoes an interim reposing phase called G0 phase which is followed by preparation of cell division through G1, S, and G2 phases which are further followed by next mitotic division [21,23] This cyclic order of physiological events comprising the mitotic division, reposing phase and preparation of cell division followed by next mitotic division is referred as the cell cycle. The transition from G0 to G1 phase of a cell cycle is tightly regulated by the balancing activity of positive signal engendered from mitogenic signals like magnification factors, hormones, amino acids and negative signals originated from Cyclin Inhibitory Proteins (CIPs) and Kinase Inhibitory Proteins (KIPs) [24,25]. At physiological state, positive signals subsist at their basal level and negative signals at their peak level in undivided somatic cells at G0 phase whereas the cells enter G1 phase only when negative signals minimize and positive signals reach their peak [26]. The length of the G0 phase varies from cell type to cell type. For example, while neuronal cells may have perennial G0 phase, the White Blood Cells (WBC) may have G0 phase for the only a couple of days. In contrast, cancer cells may have a very short span of G0 phase or none at all [26,27]. This designates that cancer cells are always in active cell cycle and cell division occurs perpetually irrespective of the presence of magnification promoting positive signals or absence of negative signals in the cellular environment. Mutation in the positive signaling molecules (e.g. magnification factor receptors) or negative signaling molecules (e.g P53) may be one of the vital reasons for this kind of uninterrupted, perpetual cell division of cancer cells [26,28].

Consequently, regulation of cell cycle is most paramount to regulate uncontrolled and aberrant proliferation of cancer cells. Quer and UA have been studied in sundry cancer cell lines and in in-vivo cancer models and declared as cell cycle inhibitors [29,30]. Up- and down-regulation of sundry cell cycle inhibitors and other regulatory proteins in the presence of these phytochemicals have been noted in various experiments. The present review summarizes the all known mechanisms of cell cycle inhibition by Quer and UA.

Chemistry of Quercetin and Ursolic Acid

Quer (3,5,7,3’,4’–Penta hydroxy flavone) is a flavonol belonging to the class of polyphenolic flavonoids which is characterized by the presence of five hydroxyl groups on C6-C3-C6 backbone structure especially a 3-OH group on the pyrone ring (ring C) [31]. It is the most important and abundant flavonol being found in apples, onions, and blueberries at a higher level while in form of glycoside [32-34]. It is synthesized by two methods: (i) By the cyclization of chalcone of 2,4-dimethoxy-6-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde; (ii) The condensation of ω-Methoxyphloroacetophenone with a veratric anhydride in the presence of the potassium salt of 3,4-dimethoxybenzoic acid [35].

UA (3β-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid (C30) of ursane (α-amyrin) and it consists five cycles of six-membered rings with trans junction of rings like A/B, B/C, C/D and the cis junction of rings such as D/E. In this molecule, one hydroxyl group is attached at the C-3 position, one carboxylic group at C-17 and a double bond is present at C-12 while the seven methyl groups are linked at C-4, C-4, C-8, C-10, C-14 C-19 and C-20. The main sources of UA are reported to be berries and peels of fruits and its acetate derivative was synthesized from α-amyrinbenzoate [36,37] (Figure 1).