Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549
Authors: Dong Jiang
Jun Zhao
Yin Li
Shi-Ying Zheng
Jin-Feng Ge
Journal: Molecular Medicine Reports (2011)
Discipline: CLINICAL MEDICINE
Keywords: quercetin; apoptosis; bcl-2; bax.
Affiliations: Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, PR China. 

Abstract:  The aim of the present study was to investigate the anticancer effect of quercetin (QC) in the human lung cancer cell line A-549 and further study the mechanism of apoptosis induction by QC. Low differentiation potential A-549 human lung cancer cells were treated with QC at different doses and for different times, and the growth inhibitory rates were detected by MTT assay. Apoptosis induced by QC in A-549 cells was observed by Annexin V/PI double staining and flow cytometric assay. The relative tumor growth ratio of the treated/control tumors (T/C) (%) was chosen to represent the tumor growth inhibition of A-549 cell nude mouse xenografts by QC. Apoptosis of the nude mouse xenografts was observed by Annexin V/PI double staining and flow cytometric assay and DNA fragmentation assay. To further determine the molecular mechanism of apoptosis induced by QC, changes in the expression of bcl-2 and bax genes were detected by RT-PCR. Following incubation with QC, the cell growth of the low differentiation potential A-549 human lung cancer cells was dramatically inhibited in a dose-dependent manner. After the cells were exposed to QC for 24, 48 and 72 h, the IC50 value was 1.02 ¬± 0.05, 1.41 ¬± 0.20 and 1.14 ¬± 0.19 ¬µmol/l, respectively. Apoptosis in the A-549 cells induced by QC was noted. The apoptotic subpopulation of A-549 cells was approximately 12.96 and 24.58%, respectively, when cells were incubated with 1.2 ¬µmol/l QC for 48 and 72 h. T/C (%) of A-549 nude mouse xenografts was 44.3, when the nude mice were treated with QC (8 mg/kg). Meanwhile, apoptosis induced by QC was observed in the A-549 nude mouse xenografts. Increased expression of the bax gene and decreased expression of the bc1-2 gene were noted using RT-PCR. Our results provide further evidence of the growth inhibition of the A-549 human lung adenocarcinoma cancer cell line by QC. This effect is associated with the induction of apoptosis in A-549 cells and the molecular mechanism may be related to the reduction in expression of the apoptosis-regulating gene bcl-2, and increase in expression of the apoptosis-regulating gene bax. These results were also confirmed in vivo. 

Retracted: No

PubPeer comments:
  QC is one of the most widely distributed bioflavonoids in the plant kingdom and is a common component of most edible fruits and vegetable. Humans consume approximately 1 g of dietary flavonoid daily. This compound has been shown to inhibit the growth of various human cancer cell lines (1-3), including leukemia, hepatocellular carcinoma, and estrogen receptor-positive breast carcinoma MCF-7 cells, suggesting that QC may have anticancer and anti-metastatic potential (4-6). The growth inhibitory effect of QC on tumor cells is found to be a consequence of its ability to interfere with the enzymatic processes involved in the regulation of cellular proliferation: DNA, RNA and protein biosynthesis (7,8). QC has also been shown to down-regulate or inhibit the phosphatidylinositol and phosphatidylinositol phosphate kinase activities in human carcinoma cells, leading to a marked reduction in second messenger IP3 concentration and cell death (9,10). Therefore, QC may be useful in the treatment of carcinomas with increased or down-regulated signal transduction capacity (10-12). Compare with [Shi et al (2003)] :  Quercetin (3,3u2019,4u2019,5,7-pentahydroxyflavone) is one of most widely distributed bioflavonoids in the plant kingdom and is a common component of most edible fruits and vegetable. Humans consume approximately 1 g of dietary flavonoid daily. This compound has been shown to inhibit the growth of various human cancer cell lines[26-34], including leukemia, hepatocellular carcinoma, and estrogen-receptor positive breast carcinoma MCF-7, suggesting that quercetin may have anti-cancer and anti-metastasis potential[35-39]. The growth inhibitory effect of quercetin on tumor cells is found to be consequence of its ability to interfere with the enzymatic processes involved in the regulation of cellular proliferation: DNA, RNA and protein biosynthesis[40-43]. Quercetin also has shown to down-regulate or inhibit the phosphatidylinositol (PI) and phosphatidylinositol phosphate (PIP) kinase activities in human carcinoma cells, leading to a marked reduction of second messengers IP3 concentration and cell death[44,45]. Therefore, quercetin may be useful in the treatment of carcinomas with increased or down-regulated signal transduction capacity[45-47]. , 
 From the Discussion:  QC is a flavonoid molecule ubiquitous in nature. In recent years, research involving QC has ranged from considering it a potentially carcinogenic agent to examination of its promise as an anticancer agent. Four pressing questions require elucidation. Is additional dietary supplementation safe? Is QC absorbed and bioavailable when administered orally? Is it active against malignant human cells and could its use be developed? Are additional routes such as intravenous or transdermal safe or more advantageous? It is the object of this review to present evidence concerning these issues and outline gaps in the available data which need to be filled in order to determine whether QC has an appreciable role in future cancer therapy . Compare with  Antioxidants and Cancer III: Quercetin ([Lamson Brignall 2000] ):  In recent years, research about quercetin has ranged from considering it potentially carcinogenic to examination of its promise as an anti-cancer agent. Four pressing questions arise. Is additional dietary supplementation safe? Is quercetin absorbed and bioavailable when given orally? Is it active against malignant human cells and could its use be developed? Are additional routes such as intravenous or transdermal safe or more advantageous? It is the object of this review to present evidence about these concerns and outline gaps in the available data which need to be filled in order to determine whether quercetin has an appreciable role in future cancer therapy. , 
 The main source, however, appears to be [Liu et al (2005)] (changing  Gambogic acid to  quercetin ). From that paper: Fig4.  Fig 5:  Fig 6.  From the present paper:  ,