Quercetin-mediated apoptosis via activation of the mitochondrial-dependent pathway in MG-63 osteosarcoma cells

Abstract

Abstract. Quercetin (a natural polyphenolic compound) is a polyphenolic flavonoid compound found in a variety of plants. It has been demonstrated to exert cytostatic activity against a variety of human cancer cell lines, including the human osteosarcoma cell line, MG-63. However, its effects on osteosarcoma cell apoptosis are still undefined. The present study was undertaken to examine the effect of quercetin on cell viability, apoptosis and mitochondrial membrane potential, and to determine the molecular mechanism of quercetininduced apoptosis by investigating the expression of Bcl-2 family proteins (Bcl-2, Bax), cytochrome C, caspase-9 and caspase-3 in MG-63 cells. We found that quercetin suppressed the viability of MG-63 cells in a dose-and time-dependent manner. Furthermore, we observed that quercetin induced the loss of mitochondrial membrane potential, upregulated the expression of the proapoptotic proteins, Bax and cytochrome C, and activated caspase-9 and caspase-3, and downregulated the expression of antiapoptotic protein, Bcl-2. These data suggest that quercetin may induce apoptosis via the mitochondrial-dependent pathway in MG-63 cells. IntroductionOsteosarcoma (OS) is the third most common cancer in childhood and adolescents, and the most common primary malignant bone tumor (1). With the development of new chemotherapy protocols, surgical techniques and radiological staging, the 5-year survival and cure rates have increased to 60-80% in patients with localized disease (2). However, major problems associated with chemotherapy still remain, particularly the frequent development of drug resistance (3). Moreover, chemotherapy may induce DNA mutations in normal cells. Hence the challenge of seeking new therapeutic approaches that can further improve the efficiency and alleviate the adverse effects is clear and urgent (4). Epidemiological studies have shown that regular consumption of tea, vegetables and fruits is associated with reduced risk of cancer (5). Quercetin with a molecular formula of C 15 H 10 O 7 (Fig. 1), is an abundant flavonoid in tea, fruits and vegetables (6). Quercetin has been shown to induce cell death by apoptosis in many human cancer cell lines, such as hepatoma, oral, leukemia, lung and colon cancer cell lines (7,8).Apoptotic cell death is an innate cellular response to eliminate abnormal or redundant cells in mammals and hence is crucial for mammal development and tissue homeostasis (9). The disturbed regulation of this vital process represents a major causative factor in the pathogenesis of cancers, including OS (10,11). The mitochondrial-dependent pathway is one of the apoptotic pathways in mammalian cells. Mitochondrial membrane permeabilization, accompanied by the collapse of electrochemical gradient across the mitochondrial membrane causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from the mitochondria, leading to cell apoptosis (12,13). Bcl-2 family proteins serve as critical regulators of this pathway through their influe...

Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep-2 cells

“…The proapoptotic activity of quercetin against cancer cells has been well documented, e.g., in leukemia (HL-60) [35], osteosarcoma (MG-63) [36], colon (LoVo) [37], breast (MCF-7, U937) [37–39], brain (MOGGCCM, T98G) [40–42], and lung (NCI-H209) [43] cell lines. Since quercetin has been examined in a variety of cancer cells, it is important to understand the effect of the flavonoid also on normal, non-malignant cells.…”

“…Several reports have proposed the mechanisms involved in the proapoptotic properties of this flavonoid consisting in activation of kinases, downregulation of survival pathways, mitochondrial potential perturbation, release of cytochrome c , and, in consequence, activation of caspase-3 and caspase-9 [18, 22, 35, 36, 38]. Experiments have shown that micromolar concentrations of quercetin in the range of 29–150 μmol/l can induce apoptosis.…”

Quercetin improves thein vitrodevelopment of porcine oocytes by decreasing reactive oxygen species levels

“…Nevertheless, the overall biological impact of quercetin remains controversial, mostly due to the limited information about its bioavailability, endogenous dynamics, and relative contribution of different types of conjugates. Some studies have showed that quercetin can mediate cancer cell apoptosis [22,25]. Furthermore, these investigations have indicated that quercetin can selectively induce apoptosis of cancer cells and not normal cells.…”

Quercetin Enhances Cisplatin Sensitivity of Human Osteosarcoma Cells by Modulating microRNA-217-KRAS Axis

“…However, in ovarian cancer cells, low concentrations of quercetin attenuate the therapeutic effects of cisplatin by reduced production of intracellular reactive oxygen species ( Li et al, 2014 ). Studies also showed that quercetin suppresses osteosarcoma cell proliferation ( Liang et al, 2011 ; Suh et al, 2010 ). However, a few researches on the effects of combined quercetin and chemotherapy on osteosarcoma, especially on their regulatory mechanism were conducted.…”