Open Access

Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models

  • Authors:
    • Jyh‑Der Leu
    • Bo‑Shen Wang
    • Shu‑Jun Chiu
    • Chun‑Yuan Chan
    • Chien‑Chih Chen
    • Fu‑Du Chen
    • Shiirevnyamba Avirmed
    • Yi‑Jang Lee
  • View Affiliations

  • Published online on: November 2, 2016     https://doi.org/10.3892/ol.2016.5345
  • Pages: 4975-4982
  • Copyright: © Leu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti‑inflammatory, antiangiogenic, anti‑invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT‑26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT‑26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2‑Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2‑Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin‑null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin‑null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

Introduction

Colorectal cancer is the third leading cause of mortality in the Western world (1) and has emerged as a common malignancy in the Asian population as a result of changes in diet and physical activity levels (2). Dietary habits have been related to the risk of colorectal cancer (3,4). Surgery and chemotherapy are the primary treatments for colorectal cancer. Radiotherapy is a typical adjuvant treatment after surgery or chemotherapy for high-stage colorectal cancers (5,6). However, colorectal carcinomas display a wide range of radiosensitivity (7,8). Therefore, new approaches are necessary to enhance the efficacy of radiation treatments for colorectal cancers.

Previous epidemiological studies have shown that the daily inclusion of fruit and vegetables in the diet decreases the risk of colon cancer (9). In addition, it has been reported that flavonoids, which are abundant in numerous plants, protect against a number of tumorigenic processes, including oxidative stress, inflammation, angiogenesis and cell invasion (1012). Furthermore, flavonoids induce cell cycle arrest, apoptosis and radiosensitivity in cancer cells in vitro (1315). The flavonoid fisetin (3,7,3′,4′-tetrahydroxyflavone) is a polyphenol found in numerous plants. A number of previous reports have shown that fisetin activates p53 activity, and represses the cyclooxygenase-2 and Wnt/epidermal growth factor receptor/nuclear factor-B signaling pathways in human cancer cells to promote apoptosis (14,1618). In addition, fisetin inhibits the spindle checkpoint response that arrests cells in the radiosensitive G2/M phase (19,20). However, the in vivo effects of fisetin remain unclear. As fisetin is a natural and edible product with acceptable biosafety, the clinical potential of this compound is of particular interest and warrants further investigation.

Securin, which was originally isolated from rat pituitary tumor cells, is alternatively called the pituitary tumor transforming gene (21). Securin is a multi-functional protein that serves a number of biological roles, such as the regulation of cellular transformation, sister chromatid separation (22,23), gene transcription (24) and DNA damage repair (25,26). Notably, securin interacts with p53 and perturbs p53-mediated transcription and apoptosis in tumor cells (22). Thus, securin is regarded as an oncoprotein. The depletion of securin has been reported to sensitize human colorectal cancer cells to various types of treatment, including fisetin, butein and ionizing radiation (2729). However, whether these effects can be repeated in vivo is unknown.

In the present study, tumor-bearing mice were used to examine the effect of fisetin alone and in combination with radiation on the growth of colorectal tumors in vivo. In addition, tumors with defective securin expression were assessed to investigate if securin depletion would enhance sensitivity to these treatments.

Materials and methods

Cell culture

Murine CT-26 colon cancer cells, and human HCT116WT, HCT116p53-/−, HCT116securin-/− and p53-R273H mutant HT-29 colorectal cancer cell lines (30) were cultured in RPMI-1640 medium (Thermo Fisher Scientific, Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific Inc.), 100 U/ml penicillin, 100 µg/ml streptomycin and 1 mM sodium pyruvate. Cultures were maintained at 37°C in a 95% humidified incubator (Thermo Fisher Scientific, Inc.) with 5% CO2 and passaged at 1:3 every 2 days.

Mouse xenograft models

A total of 62 male BALB/c nude mice (weight, 20 g; age, 6 weeks) were purchased from the National Laboratory Animal Center (NLAC, Nankang, Taipei, Taiwan). The mice were maintained at 22–24°C and 70% humidity under a 12-h light/dark cycle. Food and water were available ad libitum. Five mice were kept in each 77.4×77.4-cm cage. All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of National Yang-Ming University (Taipei, Taiwan; approval no. 1001270). Prior to tumor xenografting, mice were anesthetized with ketamine (50 mg/kg; IMALGENE®; Merial Laboratoire de Toulouse, Lyon, France) and xylazine (15 mg/kg; Sigma-Aldrich; Merck Millipore, Darmstadt, Germany). Subsequently, CT-26 (1×106) or HCT116 (2×106) cells were subcutaneously injected into the hind legs of the mice (n=5 for injection of each cell line). Prior to further treatment, mice were maintained until tumors reached 100 mm3. Tumor volume was measured using a caliper and calculated as the following: (Length × width2) / 2. Tumor volume was measured every 2–3 days to draw tumor growth curves followed by measurement of body weight.

Reagents and radiation treatments

Fisetin was purchased from Sigma-Aldrich (Sigma-Aldrich) and intratumorally injected at a dose of 5 mg/kg on days 0 and 7. Tumors were irradiated with 2 Gy/day for 5 days using an X-ray machine (RS 2000 Biological Research X-ray Irradiator; Rad Source Technologies, Inc., Suwanee, GA, USA) operating at 160 kVp and 25 mA. The dose rate at a source to subject distance of 38 cm was 1.83 Gy/min. For combined fisetin and radiation treatment, mice were treated with 5 mg/kg fisetin followed by 2 Gy irradiation on days 0 and 7. For the control group, the mice were injected with DMSO at the same volume of dissolved fisetin on days 0 and 7. Five mice were used in each group. These treatments are illustrated on a timeline in Fig. 1. Excluding the tumor site, all areas of the mice were masked using a lead radiation protector.

Western blotting and antibodies

Western blot analysis was performed as described previously (29). The following primary antibodies were used: Anti-p53 (Cat. no. GEX70214; 1:2,000; GeneTex, Inc., Irvine, CA, USA), anti-securin (Cat. no. ab3305; 1:1,000; Abcam, Cambridge, UK) and anti-GAPDH (Cat. no. PB197650; 1:5,000; Thermo Fisher Scientific Inc.). The secondary antibodies included a goat anti-mouse antibody (Cat. no. AP124P; 1:10,000; EMD Millipore, Billerica, MA, USA) for detecting the anti-securin and anti-GAPDH primary antibodies, and a goat anti-rabbit antibody (Cat. no. AP132P; 1:10,000; EMD Millipore) for detecting the anti-p53 primary antibody. Band intensities were measured by densitometry using ImageJ 1.x software (National Institutes of Health, Bethesda, MD, USA) (31).

Cell proliferation measurement

Cells (1×105) were seeded into 6-cm culture dishes and collected for hemocytometric calculation every day for 7 days. For each time point, the mean number of cells was calculated from three independent cell cultures. The results were plotted as cell proliferation curves.

Statistical analysis

Results are presented as the mean ± standard deviation. A Student's t-test was performed to determine if differences between groups were statistically significant. For survival analysis, the Kaplan-Meier estimator was used and the results were analyzed using the log-rank test. Statistical analyses were performed using GraphPad Prism 3.0 software (GraphPad Software, Inc., La Jolla, CA, USA). P<0.05 was considered to indicate a statistically significant difference.

Results

Fisetin inhibits tumor growth in a mouse CT-26 xenograft model

To examine the effect of fisetin on colorectal cancer growth in vivo, a mouse tumor xenograft model generated by injection of CT-26 colon cancer cells was treated with fisetin. Compared with the untreated control group, a single intratumoral injection of 5 mg/kg fisetin significantly reduced tumor volume for the following 10 days (Fig. 2A). As tumors appeared to re-grow 6 days after the first injection, a second dose of fisetin was administered on day 11 to examine if tumor growth could be inhibited. The results demonstrated that tumor growth was significantly suppressed for 3 days following the second administration of fisetin, as compared with the control group (Fig. 2A), although tumor growth was not completely inhibited. Fluctuations in body weight between the control and fisetin-treated group were similar (Fig. 2B), indicating that the concentration of fisetin used in this study was not cytotoxic. In addition, the survival rate of fisetin-treated tumor-bearing mice was increased compared with the untreated control group (Fig. 2C). These results demonstrate that administration of fisetin suppresses in vivo tumor growth in a mouse CT-26 xenograft model.

Combining fisetin and radiation for the treatment of mammalian colorectal cancers

Treatment with a combination of fisetin and radiation treatment was investigated in mouse CT-26 and HCT116WT xenograft tumor models. The timeline of fisetin and radiation treatment is illustrated in Fig. 1; 2-Gy X-rays were administered to the tumor site five times between the first and second fisetin treatments to mimic a clinical regime. The results showed that CT-26 tumor growth was suppressed by fisetin and radiation alone; however, this effect was enhanced by combining the two treatments at 16 to 29 days following treatment (Fig. 3A). Body weight was not significantly different between any of the groups, suggesting that combined fisetin/radiation treatment did not cause systemic toxicity (Fig. 3B). In addition, HCT116 tumor growth was completely and significantly inhibited by combined fisetin/radiation treatment (P<0.05 vs. the control group; Fig. 3C), without significant loss of body weight (Fig. 3D). These results suggest that combined fisetin and radiation treatment is highly effective in suppressing colorectal cancer.

Fisetin induces p53 and suppresses securin protein expression in human colorectal cancer cells

p53 is a tumor suppressor protein that is regulated by a number of different proteins. A previous study demonstrated that the securin oncoprotein binds to p53 and modulates its activity (32). Although securin protein levels have been reported to be elevated by radiation independently of p53 activity (27), it is unknown whether fisetin influences the expression of p53 or securin. In the present study, an experiment with a series of fisetin doses was performed to investigate whether fisetin influences the expression of p53 and securin in different human colorectal cancer cell lines. The results identified that in HCT116WT cells, p53 protein levels were increased and securin protein levels were decreased following fisetin treatment (Fig. 4A). Interestingly, fisetin increased the expression of p53 in HCT116securin-/− cells and decreased the expression of securin in HCT116p53-/− cells (Fig. 4A). In p53 mutant HT-29 cells, fisetin downregulated the expression of securin protein (Fig. 4A). Quantification of the protein bands on the Western Blot analysis revealed the same results (Fig. 4B). These results indicate that fisetin increases the expression of p53 and decreases the expression of securin, which suppresses tumor growth. Furthermore, fisetin-mediated expression of p53 and securin was independent of the expressive status of p53/securin (null or wild-type).

Effect of fisetin and radiation combination treatment on securin-null colorectal cell-formed xenograft tumors

As fisetin could induce the expression of the p53 protein in the absence of securin, the ability of fisetin and radiation treatment to suppress tumor growth in vivo was investigated. Firstly, the growth curves of HCT116WT and HCT116securin-/− cells were compared, which showed that the proliferation of HCT116securin-/− cells was significantly slower than that of HCT116WT cells after 3 days of proliferation (Fig. 5A). Tumor growth was moderately suppressed by fisetin treatment in HCT116securin-/− cells; however, no significant advantage was observed following fisetin and radiation combination treatment (Fig. 5B). The body weight of the mice following fisetin, radiation and fisetin/radiation showed no significant difference compared with the control group (Fig. 5C). Therefore, depletion of securin does not enhance the effects of fisetin and radiation combination treatment on colorectal tumors in vivo. However, a larger sample size is necessary to validate this result.

Discussion

Previous studies have shown that fisetin possesses a wide range of activities to suppress the growth of human cancer cells, including breast, prostate, bladder, lung, melanoma and colorectal cancer cells (16,3339). Among these types of cancer, colorectal cancer is particularly interesting with regards to fisetin, since fisetin is a nutrient supplement that can be administrated orally (40). It is thought that fisetin is absorbed through the digestive tract without the need for intravascular injection (41). Although in vitro studies have demonstrated the efficacy of fisetin in the treatment of colorectal cancer (15,16), few in vivo studies have been reported. Since preclinical studies are essential for potent therapeutic agents to be accepted for clinical trials, the experimental animal data in the present study is important for evaluating the application of fisetin to colorectal cancer therapy. In addition, the current study investigated whether fisetin treatment combined with ionizing radiation exerted synergistic effects. A previous study reported that a combination of cisplatin and fisetin exerted anticancer activity in embryonic carcinoma cells in vitro and in vivo (42). Although radiotherapy is not typically used in the treatment of colorectal cancer, it is frequently applied to adjuvant chemotherapy in rectal cancer (43,44). The combination of fisetin and radiotherapy is an interesting alternative adjuvant therapy, since it would likely avoid the side effects associated with chemotherapy.

In the present study, a mouse xenograft model was used to examine the tumor-suppressive efficacy of fisetin in vivo on colon and colorectal cancers. Animal (CT-26) and human (HCT116) colon and colorectal cancer cells, respectively, were used to establish xenograft tumor models. Fisetin treatment was shown to suppress the growth of tumors formed by CT-26 cells, but not HCT116 cells. However, treatment with fisetin combined with radiation exhibited enhanced tumor suppressive effects on CT-26 and HCT116 xenograft tumors. This finding supports the potential application of fisetin to adjuvant radiotherapy for colorectal cancers. As fisetin did not exert toxicity in the current study, or in other reports (45,46), its use as an adjuvant treatment should be feasible.

In the present study, CT-26 and HCT116 cell lines, which express wild-type p53, formed tumors that were sensitive to radiation treatment. Since p53 is known to be upregulated by radiation (47), it is reasonable that this phenomenon was observed in vivo in the present study. Importantly, the current study used clinically comparable fractionated radiation of 2-Gy/day/fraction for 5 days (48). Compared with this regime, the fisetin-combined radiation treatments only irradiated tumors at 2 Gy twice in one week, yet remained more efficient than the fractionated radiation on tumor suppression, suggesting that fisetin enhances the tumor response to radiation in vivo. Thus, the use of fisetin in adjuvant radiotherapy may reduce total radiation exposure and improve the quality of life of patients during and following treatment. Further investigations into the optimal combination for colorectal cancer therapy are warranted.

The genetic background of a tumor is known to influence the prognosis (49,50). The authors of the present study were interested in p53 and securin because of the results of our previous studies (15,27). Briefly, fisetin was shown to enhance the radiosensitivity of p53-mutant human HT-29 colorectal cancer cells, and promote apoptosis in securin-depleted human HCT-116 colorectal cancer cells. Consistent with a previous report (14), in the present study, we also showed that fisetin could induce p53 protein expression in wild-type and securin-null HCT116 cells. Furthermore, expression of the securin protein was downregulated by fisetin regardless of the p53 expression status. In addition, in the current study xenograft securin-null colorectal tumors exhibited increased sensitivity to fisetin compared with the untreated control. However, individual variance in the tumor-bearing mice may have reduced the extent of tumor suppression resulting from fisetin treatment. Therefore, an increased sample size is required to validate the effect of fisetin on securin-null colorectal cancers. In addition, this limitation should be considered for the investigation of fisetin and radiation combination treatment. In the current study, p53 protein expression was still induced in securin-null HCT116 cells by fisetin, indicating that p53 and securin protein expression should be modulated by fisetin and radiation combination treatment in order to achieve optimal tumor suppression.

In conclusion, the present study used mouse xenograft tumor models to investigate the effect of fisetin alone or in combination with radiation on colon and colorectal tumor growth. The results showed that fisetin treatment alone was sufficient to suppress murine CT-26 colon tumors, but not human HCT116 colorectal tumors. Interestingly, a combination of fisetin and radiation treatment enhanced the tumor suppression compared with fractionated irradiation alone. In addition, the results of the current study revealed that securin-null HCT116 tumors exhibited increased sensitivity to fisetin treatment, although this observation needs to be validated in a larger sample set. Investigating whether securin is the key molecule in mediating the effects of fisetin and radiation combination treatment on colon and colorectal cancers warrants future exploration. To the best of our knowledge, this is the first report demonstrating the therapeutic efficacy of fisetin and radiation combination treatment on colon and colorectal cancer in vivo. The results of the present study provide important preclinical information for evaluating the potential use of fisetin in adjuvant cancer radiotherapy.

Acknowledgements

The present study was supported by the Taipei City Government Department of Health (Taipei, Taiwan; grant no. 10101-62-034) and the Ministry of Science and Technology (Taipei, Taiwan; grant nos. 102-2628-B-010-012-MY3 and 105-2628-B-010-013-MY3).

References

1 

Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Davies NJ, Batehup L and Thomas R: The role of diet and physical activity in breast, colorectal, and prostate cancer survivorship: A review of the literature. Br J Cancer. 105:(Suppl 1). S52–S73. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Doll R and Peto R: The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 66:1191–1308. 1981.PubMed/NCBI

4 

Lin J, Zhang SM, Cook NR, Rexrode KM, Liu S, Manson JE, Lee IM and Buring JE: Dietary intakes of fruit, vegetables, and fiber, and risk of colorectal cancer in a prospective cohort of women (United States). Cancer Causes Control. 16:225–233. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Hamaya Y, Guarinos C, Tseng-Rogenski SS, Iwaizumi M, Das R, Jover R, Castells A, Llor X, Andreu M and Carethers JM: Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer. PLoS One. 10:e01275912015. View Article : Google Scholar : PubMed/NCBI

6 

Saltz LB and Minsky B: Adjuvant therapy of cancers of the colon and rectum. Surg Clin North Am. 82:1035–1058. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Allal AS, Kähne T, Reverdin AK, Lippert H, Schlegel W and Reymond MA: Radioresistance-related proteins in rectal cancer. Proteomics. 4:2261–2269. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Ma W, Yu J, Qi X, Liang L, Zhang Y and Ding Y, Lin X, Li G and Ding Y: Radiation-induced microRNA-622 causes radioresistance in colorectal cancer cells by down-regulating Rb. Oncotarget. 6:15984–15994. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Lock K, Pomerleau J, Causer L, Altmann DR and McKee M: The global burden of disease attributable to low consumption of fruit and vegetables: Implications for the global strategy on diet. Bull World Health Organ. 83:100–108. 2005.PubMed/NCBI

10 

Martinez-Perez C, Ward C, Cook G, Mullen P, McPhail D, Harrison DJ and Langdon SP: Novel flavonoids as anti-cancer agents: Mechanisms of action and promise for their potential application in breast cancer. Biochem Soc Trans. 42:1017–1023. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Orlikova B, Menezes JC, Ji S, Kamat SP, Cavaleiro JA and Diederich M: Methylenedioxy flavonoids: Assessment of cytotoxic and anti-cancer potential in human leukemia cells. Eur J Med Chem. 84:173–180. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Imai M, Kikuchi H, Denda T, Ohyama K, Hirobe C and Toyoda H: Cytotoxic effects of flavonoids against a human colon cancer derived cell line, COLO 201: A potential natural anti-cancer substance. Cancer Lett. 276:74–80. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Lu X, Jung JI, Cho HJ, Lim DY, Lee HS, Chun HS, Kwon DY and Park JH: Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr. 135:2884–2890. 2005.PubMed/NCBI

14 

Lim DY and Park JH: Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol. 296:G1060–G1068. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Chen WS, Lee YJ, Yu YC, Hsaio CH, Yen JH, Yu SH, Tsai YJ and Chiu SJ: Enhancement of p53-mutant human colorectal cancer cells radiosensitivity by flavonoid fisetin. Int J Radiat Oncol Biol Phys. 77:1527–1535. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Suh Y, Afaq F, Johnson JJ and Mukhtar H: A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 30:300–307. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H and Tian B: Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 108:84–93. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Chou RH, Hsieh SC, Yu YL, Huang MH, Huang YC and Hsieh YH: Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PloS one. 8:e719832013. View Article : Google Scholar : PubMed/NCBI

19 

Salmela AL, Pouwels J, Varis A, Kukkonen AM, Toivonen P, Halonen PK, Perälä M, Kallioniemi O, Gorbsky GJ and Kallio MJ: Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis. 30:1032–1040. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE and Klotz LH: Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 9:68–76. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Pei L and Melmed S: Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 11:433–441. 1997. View Article : Google Scholar : PubMed/NCBI

22 

Rustgi AK: Securin a new role for itself. Nat Genet. 32:222–224. 2002. View Article : Google Scholar : PubMed/NCBI

23 

Zou H, McGarry TJ, Bernal T and Kirschner MW: Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 285:418–422. 1999. View Article : Google Scholar : PubMed/NCBI

24 

Tong Y and Eigler T: Transcriptional targets for pituitary tumor-transforming gene-1. J Mol Endocrinol. 43:179–185. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Kim DS, Franklyn JA, Smith VE, Stratford AL, Pemberton HN, Warfield A, Watkinson JC, Ishmail T, Wakelam MJ and McCabe CJ: Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity. Carcinogenesis. 28:749–759. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Nagao K, Adachi Y and Yanagida M: Separase-mediated cleavage of cohesin at interphase is required for DNA repair. Nature. 430:1044–1048. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Yu SH, Yang PM, Peng CW, Yu YC and Chiu SJ: Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. Cancer Lett. 300:96–104. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Huang YT, Lin CI, Chien PH, Tang TT, Lin J and Chao JI: The depletion of securin enhances butein-induced apoptosis and tumor inhibition in human colorectal cancer. Chem Biol Interact. 220:41–50. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Chen WS, Yu YC, Lee YJ, Chen JH, Hsu HY and Chiu SJ: Depletion of securin induces senescence after irradiation and enhances radiosensitivity in human cancer cells regardless of functional p53 expression. Int J Radiat Oncol Biol Phys. 77:566–574. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve M, Damalas A, Blandino G and Haupt Y: Promyelocytic leukemia protein is required for gain of function by mutant p53. Cancer Res. 69:4818–4826. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Schneider CA, Rasband WS and Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 9:671–675. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Bernal JA, Luna R, Espina A, Lázaro I, Ramos-Morales F, Romero F, Arias C, Silva A, Tortolero M and Pintor-Toro JA: Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet. 32:306–311. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Yang PM, Tseng HH, Peng CW, Chen WS and Chiu SJ: Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int J Oncol. 40:469–478. 2012.PubMed/NCBI

34 

Khan N, Afaq F, Syed DN and Mukhtar H: Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis. 29:1049–1056. 2008. View Article : Google Scholar : PubMed/NCBI

35 

Li J, Qu W, Cheng Y, Sun Y, Jiang Y, Zou T, Wang Z, Xu Y and Zhao H: The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin Pharmacol Toxicol. 115:321–329. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Kang KA, Piao MJ and Hyun JW: Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway. In Vitro Cell Dev Biol Anim. 51:300–309. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Syed DN, Chamcheu JC, Khan MI, Sechi M, Lall RK, Adhami VM and Mukhtar H: Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: Findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol. 89:349–360. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Pal HC, Sharma S, Strickland LR, Katiyar SK, Ballestas ME, Athar M, Elmets CA and Afaq F: Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFκB signaling pathways. PloS one. 9:e863382014. View Article : Google Scholar : PubMed/NCBI

39 

Szliszka E, Helewski KJ, Mizgala E and Krol W: The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells. Int J Oncol. 39:771–779. 2011.PubMed/NCBI

40 

Khan N, Syed DN, Ahmad N and Mukhtar H: Fisetin: A dietary antioxidant for health promotion. Antioxid Redox Signal. 19:151–162. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Sahu BD, Kumar JM and Sistla R: Fisetin, a dietary flavonoid, ameliorates experimental colitis in mice: Relevance of NF-κB signaling. J Nutr Biochem. 28:171–182. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Tripathi R, Samadder T, Gupta S, Surolia A and Shaha C: Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. 10:255–268. 2011. View Article : Google Scholar : PubMed/NCBI

43 

Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, et al: Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: A dutch colorectal cancer group (DCCG) randomized phase III trial. Ann Oncol. 26:696–701. 2015. View Article : Google Scholar : PubMed/NCBI

44 

Colorectal Cancer Collaborative Group, . Adjuvant radiotherapy for rectal cancer: A systematic overview of 8,507 patients from 22 randomised trials. Lancet. 358:1291–1304. 2001. View Article : Google Scholar : PubMed/NCBI

45 

Currais A, Prior M, Dargusch R, Armando A, Ehren J, Schubert D, Quehenberger O and Maher P: Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. Aging Cell. 13:379–390. 2014. View Article : Google Scholar : PubMed/NCBI

46 

da Costa MP, Bozinis MC, Andrade WM, Costa CR, da Silva AL, de Oliveira CM Alves, Kato L, Ode F Fernandes, Souza LK and Mdo R Silva: Antifungal and cytotoxicity activities of the fresh xylem sap of Hymenaea courbaril L. and its major constituent fisetin. BMC Complement Altern Med. 14:2452014. View Article : Google Scholar : PubMed/NCBI

47 

Fei P and El-Deiry WS: P53 and radiation responses. Oncogene. 22:5774–5783. 2003. View Article : Google Scholar : PubMed/NCBI

48 

Fertil B and Malaise EP: Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. Int J Radiat Oncol Biol Phys. 7:621–629. 1981. View Article : Google Scholar : PubMed/NCBI

49 

Lindström LS, Hall P, Hartman M, Wiklund F and Czene K: Is genetic background important in lung cancer survival? PloS one. 4:e55882009. View Article : Google Scholar : PubMed/NCBI

50 

Ashworth A, Lord CJ and Reis-Filho JS: Genetic interactions in cancer progression and treatment. Cell. 145:30–38. 2011. View Article : Google Scholar : PubMed/NCBI

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Spandidos Publications style
Leu JD, Wang BS, Chiu SJ, Chan CY, Chen CC, Chen FD, Avirmed S and Lee YJ: Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models. Oncol Lett 12: 4975-4982, 2016.
APA
Leu, J., Wang, B., Chiu, S., Chan, C., Chen, C., Chen, F. ... Lee, Y. (2016). Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models. Oncology Letters, 12, 4975-4982. https://doi.org/10.3892/ol.2016.5345
MLA
Leu, J., Wang, B., Chiu, S., Chan, C., Chen, C., Chen, F., Avirmed, S., Lee, Y."Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models". Oncology Letters 12.6 (2016): 4975-4982.
Chicago
Leu, J., Wang, B., Chiu, S., Chan, C., Chen, C., Chen, F., Avirmed, S., Lee, Y."Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models". Oncology Letters 12, no. 6 (2016): 4975-4982. https://doi.org/10.3892/ol.2016.5345