Tanshinone IIA enhances chemosensitivity of colon cancer cells by suppressing nuclear factor-κB
- Authors:
- Published online on: January 12, 2016 https://doi.org/10.3892/etm.2016.2984
- Pages: 1085-1089
Abstract
Introduction
Colorectal cancer is the third most common type of human cancer and a major global public health concern (1). The incidence rate of colorectal cancer has been increasing in the Chinese population; in Beijing, the annual incidence of CRC has increased from 16 per 100,000 to 24 per 100,000 in the past decade (2). Chemoprevention, including the use of oxaliplatin, fluorouracil and leucovorin, is considered to be the most promising strategy, since other therapies fail to control gastrointestinal cancers (3). However, at present, no optimal adjuvant chemotherapy exists; therefore, there is a constant requirement for the development of rationally designed, novel adjuvant therapeutic strategies for the treartment of colon cancer. In the past few decades, traditional Chinese herbal medicines have become a widely accepted treatment option for colorectal cancer and an increasing number of studies have focused on the identification of new bioactive pure compounds and herbs (4,5). Danshen, also known as Radix Salviae miltiorrhiza, is widely prescribed in traditional Chinese medicine for the treatment of cardiovascular diseases (6,7). Tanshinone IIA (TSA; C19H18O3) is extracted from Danshen (8,9) and presents anti-inflammatory (10,11) and antioxidant properties (12,13). Recently, TSA has been proven to also harbor antitumor activities in various human malignant neoplasms (14–17). Su et al reported that TSA may inhibit cell growth and induce apoptosis in colon cancer (18); however, the molecular mechanisms of TSA action remain unclear. In the present study, the influence and molecular mechanism of TSA on colon cancer cell growth and chemosensitivity of colon cancer cells to fluorouracil (5-FU) were investigated.
Materials and methods
Cell culture and materials
HCT1116 and COLO205 colon cancer cells were purchased from American Type Culture Collection (Manassas, VA, USA). The cells were cultured in RPMI-1640 medium (Gibco-BRL, Gasthersburg, MD, USA) supplemented with 10% heat-inactivated fetal bovine serum (Gibco-BRL) and 2% penicillin/streptomycin (penicillin, 10,000 U/ml; streptomycin, 10 mg/ml). The cells were placed into tissue culture flasks (75 cm2, 250 ml) and grown at 37°C in humidified atmosphere consisting of 5% CO2 and 95% air. TSA was purchased from Dasherb Corp. (Shenyang, China). Aprotinin and leupeptin were obtained from Sigma-Aldrich (St. Louis, MO, USA). Dimethyl sulfoxide was purchased from EMD Millipore Corporation (Darmstadt, Germany). The antibodies used in the present study were the following: Mouse monoclonal anti-actin (1:1,000; cat. no. sc-8432; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), rabbit polyclonal anti-vascular endothelial growth factor (VEGF; 1:500; cat. no. ab46154; Abcam, Cambridge, MA, USA), rabbit polyclonal anti-c-Myc (1:1,000; cat. no. 9402S; Cell Signaling Technology, Inc., Denvers, MA USA), mouse monoclonal anti-cyclooxygenase-2 (COX2; 1:1,000; cat. no. sc-376861) and rabbit polyclonal anti-B-cell lymphoma-2 (Bcl-2; 1:2,000; cat. no. sc-492) (both from Santa Cruz Biotechnology Inc.).
Cell viability assay
Cell viability was measured using a Cell Counting kit (CCK)-8 kit (Dojindo Molecular Technologies, Inc., Kumamoto, Japan). Briefly, cells were seeded in a 94-well plate at a density of 2×104 cells per well in 200 µl culture medium. The following day the cells were incubated with drug for 48 h. At the end of the experiment, 20 µl CCK-8 solution was added to the cells. The cells were then further incubated at 37°C for 2 h. Subsequently, the optical density (OD) at 450 nm was measured using a VICTOR™ × Multi-Label reader (PerkinElmer, Inc., Waltham, MA, USA) and the percentage of cell viability was calculated as ODdrug/ODcontrol × 100%.
Preparation of nuclear extract
Following treatment, the cells were harvested and washed twice with ice-cold phosphate-buffered saline (PBS). Next, the cell samples were resuspended in 1 ml PBS and nuclear extracts were prepared on ice as described in a previous study (19). Following centrifugation at 15,000 × g for 10 min at 4°C, the cell pellet was suspended in an ice-cold buffer (consisting of 10 mmol/l HEPES, 1.5 mmol/l MgCl2, 0.5 mmol/l dithiothreitol, 0.2 mmol/l phenylmethylsulphonylfluoride and 0.2 mmol/l KCl), vortexed for 10 sec and centrifuged at 15,000 × g for 5 min at 4°C. Subsequently, the nuclear pellet was washed in 1 ml buffer (consisting of 20 mmol/l HEPES, 25% glycerol, 0.2 mmol/l ethylenediaminetetraacetic acid, 1.5 mmol/l MgCl2 and 0.42 mol/l hypertonic saline), resuspended in 30 ml buffer (20 mmol/l HEPES, 25% glycerol, 0.42 mol/l NaCl, 1.5 mmol/l MgCl2, 0.2 mmol/l EDTA), rotated for 30 min at 4°C and centrifuged at 14,500 × g for 20 min at 4°C. Finally, the supernatants were used as nuclear extracts.
Western blotting
Whole cell lysates or nuclear extracts were separated using 12% SDS-PAGE, as described previously (20). Transfer buffer [25 mM Tris (pH 8.5), 20% methanol and 0.2 M glycine] was used to equilibrate the separated proteins, which were then transferred onto a 0.4-µm polyvinylidene fluoride membrane (EMD Millipore Corporation, Bedford, MA, USA). The membranes were incubated with 5% non-fat dry milk in Tris-buffered saline containing 0.1% Tween-20 for 1 h, followed by washing and then incubation with appropriate dilutions of specific primary antibodies at 4°C overnight. Following incubation with secondary anti-mouse peroxidase-conjugated antibody (dilution, 1:15,000; Sigma-Aldrich), the immune-reactive bands were visualized using an enhanced chemiluminescence detection kit (EMD Millipore Corporation, Darmstadt, Germany). β-actin was used as an internal control for western blotting.
Statistical analysis
The statistical analysis was performed using SPSS 17.0 software (SPSS Inc., Chicago, IL, USA) and are presented as the mean ± standard deviation. One-way analysis of variance was performed to compare numeric variables between groups. P<0.05 was considered to indicate a statistically significant difference.
Results
Effect of TSA on cell viability of colon cancer cells
TSA has been demonstrated to exert an antitumor activity in numerous types of human cancer, including breast, lung, liver, prostate and ovarian cancer and leukemia (15,21–25). The data of the present study showed that the exposure of the HCT1116 and COLO205 colon cancer cell lines to TSA greatly decreased their cell viability in a concentration-dependent manner (P<0.05; Fig. 1), which suggested an antitumor effect of TSA in colon cancer.
TSA enhances chemosensitivity of colon cancer cells
Drug resistance is a clinical challenge that can result in the failure of colon cancer therapy (26). In order to examine how TSA influences the sensitivity of colon cancer cells to chemotherapy, 5-FU chemotherapy was combined with TSA treatment. As shown in Fig. 2, 5-FU-induced cell death in HCT1116 and COLO205 cells was considerably enhanced by 20 µM TSA treatment (P<0.05), which suggested that TSA was able to potentiate the chemosensitivity of colon cancer cells.
Involvement of nuclear factor-κB (NF-κB) in TSA activity
As shown by the aforementioned data, TSA can decrease cell viability and increase the chemosensitivity of colon cancer cells; however, the molecular mechanisms of TSA action remain to be elucidated. In order to further investigate the mechanisms of TSA action, the influence of TSA on the activation of NF-κB was determined, since it has been suggested that NF-κB is involved in the development and progression of various malignant neoplasms (27–33), which made it a target for tumor therapeutics (34,35). The present data revealed that 20 µM TSA treatment significantly decreased the level of phosphorylation of p65, a subunit of NF-κB (Fig. 3A), which indicated the inhibitory effect of TSA on NF-κB activation. In addition, the expression of NF-κB regulated genes was examined. As illustrated in Fig. 3B, 20 µM TSA was able to considerably decrease VEGF, c-Myc, COX-2 and Bcl-2 expression.
NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), enhances TSA activity
As indicated in Fig. 4, the inhibition of NF-κB signaling with specific inhibitor PDTC significantly potentiated the suppression of TSA-induced cell growth in HCT1116 and COLO205 cells. Furthermore, the chemosensitizing effect of TSA on colon cancer cells was also enhanced by 50 µM PDTC treatment (P<0.05), which is illustrated as increased cell growth inhibition in Fig. 4.
Discussion
Due to drug resistance and the toxic effect of current chemotherapy strategies, antitumor drug studies have been attempting to identify natural chemical compounds, and Chinese herbal medicine has been attracting increasing attention (36). TSA has been found to be an effective chemical component extracted from Danshen (Radix Salviae Miltiorrhizae) (37), which harbors anti-inflammatory and anti-oxidative activities (10–13). It has also been shown to have a cardioprotective effect by reducing apoptosis (38–40). Recently, an increasing number of studies has focused on the antitumor activity of TSA. For instance, Jung et al (41) and Liu et al (42) identified that TSA induced apoptosis in leukemic cells in vitro, possibly through the JAK/STAT3/5 and SHP1/2 pathways. In addition, Fu et al (25) found that TSA blocked the epithelial-mesenchymal transition through the downregulation of hypoxia-inducible factor-1α, reversing hypoxia-induced chemotherapy resistance in breast cancer cell lines. In addition, increasing evidence indicated that TSA can inhibit tumor cell growth and induce apoptosis (15,17,43); however, despite the fact that in certain type of cancer evidence showed that intrinsic apoptosis pathways were involved (14,44), the underlying mechanisms remain unclear. With regard to colon cancer, in 2008, Su et al identified that TSA inhibited cell growth and induced apoptosis in colon cancer cells (18). Shan et al (45) also indicated that TSA was able to inhibit colon cancer cell migration and invasion. Furthermore, in 2012 Su et al (46) found that TSA potentiated the efficacy of 5-FU in colon cancer cells in vivo through the downregulation of P-glycoprotein and LC3-II. The results of the present study confirmed the antitumor activity and chemosensitizing effect of TSA in colon cancer cells and provided new evidence that TSA can sensitize colon cancer cells to 5-FU through the suppression of NF-κB activation.
NF-κB is constitutively activated in numerous human cancer types (30–32,35). The suppression of NF-κB may induce apoptosis and sensitize cancer cells to chemotherapy (33,34,47,48). As an eukaryotic transcription factor, NF-κB regulates numerous genes that are differentially expressed and implicated in tumorigenesis, including c-Myc, COX-2 and matrix metalloproteinase-9 (49). In colon cancer, NF-κB activation participates in the promotion and progression of colon cancer (49); therefore, the aim of the present study was to investigate the effect of TSA on NF-κB activation and on NF-κB-regulated gene products. The results showed that TSA treatment decreased the level of the phosphorylated p65 in the nucleus of colon cancer cells and the NF-κB-regulated gene expression levels of VEGF, COX-2, c-Myc and Bcl-2. In addition, the inhibition of NF-κB with specific inhibitor PDTC may further enhance the induction of cell death and the chemosensitizing effect of TSA in colon cancer cells.
In conclusion, the present study revealed that TSA was able to induce cell death in colon cancer cells and sensitize colon cancer cells to 5-FU therapy by inhibiting NF-κB activation; therefore, TSA appears to be a good option of adjuvant chemotherapy for colon cancer.
References
Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI | |
Jin P, Wu ZT, Li SR, Li SJ, Wang JH, Wang ZH, Lu JG, Cui XJ, Han Y, Rao J and Sheng JQ: Colorectal cancer screening with fecal occult blood test: A 22-year cohort study. Oncol Lett. 6:576–582. 2013.PubMed/NCBI | |
André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, et al: Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 350:2343–2351. 2004. View Article : Google Scholar : PubMed/NCBI | |
Verhoef MJ, Balneaves LG, Boon HS and Vroegindewey A: Reasons for and characteristics associated with complementary and alternative medicine use among adult cancer patients: A systematic review. Integr Cancer Ther. 4:274–286. 2005. View Article : Google Scholar : PubMed/NCBI | |
Boon H and Wong J: Botanical medicine and cancer: A review of the safety and efficacy. Expert Opin Pharmacother. 5:2485–2501. 2004. View Article : Google Scholar : PubMed/NCBI | |
Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK and Antzelevitch C: Dimethyl lithospermate b, an extract of danshen, suppresses arrhythmogenesis associated with the brugada syndrome. Circulation. 113:1393–1400. 2006. View Article : Google Scholar : PubMed/NCBI | |
Chang PN, Mao JC, Huang SH, Ning L, Wang ZJ, On T, Duan W and Zhu YZ: Analysis of cardioprotective effects using purified Salvia miltiorrhiza extract on isolated rat hearts. J Pharmacol Sci. 101:245–249. 2006. View Article : Google Scholar : PubMed/NCBI | |
Che AJ, Zhang JY, Li CH, Chen XF, Hu ZD and Chen XG: Separation and determination of active components in Radix Salviae miltiorrhizae and its medicinal preparations by nonaqueous capillary electrophoresis. J Sep Sci. 27:569–575. 2004. View Article : Google Scholar : PubMed/NCBI | |
Zhou L, Zuo Z and Chow MS: Danshen: An overview of its chemistry, pharmacology, pharmacokinetics and clinical use. J Clin Pharmacol. 45:1345–1359. 2005. View Article : Google Scholar : PubMed/NCBI | |
Jang SI, Kim HJ, Kim YJ, Jeong SI and You YO: Tanshinone IIA inhibits LPS-induced NF-kappaB activation in raw 264.7 cells: Possible involvement of the NIK-IKK, ERK1/2, P38 and JNK pathways. Eur J Pharmacol. 542:1–7. 2006. View Article : Google Scholar : PubMed/NCBI | |
Li W, Li J, Ashok M, Wu R, Chen D, Yang L, Yang H, Tracey KJ, Wang P, Sama AE and Wang H: A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1. J Immunol. 178:3856–3864. 2007. View Article : Google Scholar : PubMed/NCBI | |
Lin R, Wang WR, Liu JT, Yang GD and Han CJ: Protective effect of tanshinone IIA on human umbilical vein endothelial cell injured by hydrogen peroxide and its mechanism. J Ethnopharmacol. 108:217–222. 2006. View Article : Google Scholar : PubMed/NCBI | |
Wang AM, Sha SH, Lesniak W and Schacht J: Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo. Antimicrob Agents Chemother. 47:1836–1841. 2003. View Article : Google Scholar : PubMed/NCBI | |
Tian HL, Yu T, Xu NN, Feng C, Zhou LY, Luo HW, Chang DC, Le XF and Luo KQ: A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway. Cancer Lett. 297:18–30. 2010. View Article : Google Scholar : PubMed/NCBI | |
Zhang J, Wang J, Jiang JY, Liu SD, Fu K and Liu HY: Tanshinone IIA induces cytochrome c-mediated caspase cascade apoptosis in A549 human lung cancer cells via the JNK pathway. Int J Oncol. 45:683–690. 2014.PubMed/NCBI | |
Yun SM, Jung JH, Jeong SJ, Sohn EJ, Kim B and Kim SH: Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6k in KBM-5 leukemia cells. Phytother Res. 28:458–464. 2014. View Article : Google Scholar : PubMed/NCBI | |
Yang L, Guo H, Dong L, Wang L, Liu C and Wang X: Tanshinone IIA inhibits the growth, attenuates the stemness and induces the apoptosis of human glioma stem cells. Oncol Rep. 32:1303–1311. 2014.PubMed/NCBI | |
Su CC, Chen GW, Kang JC and Chan MH: Growth inhibition and apoptosis induction by tanshinone IIA in human colon adenocarcinoma cells. Planta Med. 74:1357–1362. 2008. View Article : Google Scholar : PubMed/NCBI | |
Luo P, Tan Z, Zhang Z, Li H and Mo Z: Inhibitory effects of salvianolic acid B on the high glucose-induced mesangial proliferation via NF-kappaB-dependent pathway. Biol Pharm Bull. 31:1381–1386. 2008. View Article : Google Scholar : PubMed/NCBI | |
Lui VW, Boehm AL, Koppikar P, Leeman RJ, Johnson D, Ogagan M, Childs E, Freilino M and Grandis JR: Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (stat) 3. The role of stat1. Mol Pharmacol. 71:1435–1443. 2007. View Article : Google Scholar : PubMed/NCBI | |
Chen SJ: A potential target of Tanshinone IIA for acute promyelocytic leukemia revealed by inverse docking and drug repurposing. Asian Pac J Cancer Prev. 15:4301–4305. 2014. View Article : Google Scholar : PubMed/NCBI | |
Chiu SC, Huang SY, Chen SP, Su CC, Chiu TL and Pang CY: Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo. Prostate Cancer Prostatic Dis. 16:315–322. 2013. View Article : Google Scholar : PubMed/NCBI | |
Won SH, Lee HJ, Jeong SJ, Lü J and Kim SH: Activation of p53 signaling and inhibition of androgen receptor mediate tanshinone IIA induced G1 arrest in LNCaP prostate cancer cells. Phytother Res. 26:669–674. 2012. View Article : Google Scholar : PubMed/NCBI | |
Kan S, Cheung WM, Zhou Y and Ho WS: Enhancement of doxorubicin cytotoxicity by tanshinone IIA in HepG2 human hepatoma cells. Planta Med. 80:70–76. 2014. View Article : Google Scholar : PubMed/NCBI | |
Fu P, Du F, Chen W, Yao M, Lv K and Liu Y: Tanshinone IIA blocks epithelial-mesenchymal transition through HIF-1α downregulation, reversing hypoxia-induced chemotherapy resistance in breast cancer cell lines. Oncol Rep. 31:2561–2568. 2014.PubMed/NCBI | |
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N and Sarkar S: Drug resistance in cancer: An overview. Cancers (Basel). 6:1769–1792. 2014. View Article : Google Scholar : PubMed/NCBI | |
Garg A and Aggarwal BB: Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia. 16:1053–1068. 2002. View Article : Google Scholar : PubMed/NCBI | |
Yu HG, Yu LL, Yang Y, Luo HS, Yu JP, Meier JJ, Schrader H, Bastian A, Schmidt WE and Schmitz F: Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology. 65:37–45. 2003. View Article : Google Scholar : PubMed/NCBI | |
Liptay S, Weber CK, Ludwig L, Wagner M, Adler G and Schmid RM: Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer. Int J Cancer. 105:735–746. 2003. View Article : Google Scholar : PubMed/NCBI | |
Nair A, Venkatraman M, Maliekal TT, Nair B and Karunagaran D: Nf-kappaB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix. Oncogene. 22:50–58. 2003. View Article : Google Scholar : PubMed/NCBI | |
Li W, Tan D, Zenali MJ and Brown RE: Constitutive activation of nuclear factor-kappa B (NF-κB) signaling pathway in fibrolamellar hepatocellular carcinoma. Int J Clin Exp Pathol. 3:238–243. 2010. | |
Nagel D, Vincendeau M, Eitelhuber AC and Krappmann D: Mechanisms and consequences of constitutive nf-kappab activation in B-cell lymphoid malignancies. Oncogene. 11:5655–5565. 2014. View Article : Google Scholar | |
Shishodia S, Amin HM, Lai R and Aggarwal BB: Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/s arrest, suppresses proliferation and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol. 70:700–713. 2005. View Article : Google Scholar : PubMed/NCBI | |
Baldwin AS: Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 107:241–246. 2001. View Article : Google Scholar : PubMed/NCBI | |
Shen HM and Tergaonkar V: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis. 14:348–363. 2009. View Article : Google Scholar : PubMed/NCBI | |
Li X, Yang G, Li X, Zhang Y, Yang J, Chang J, Sun X, Zhou X, Guo Y, Xu Y, et al: Traditional Chinese medicine in cancer care: A review of controlled clinical studies published in chinese. PloS One. 8:e603382013. View Article : Google Scholar : PubMed/NCBI | |
Shang Q, Xu H and Huang L: Tanshinone IIA. A promising natural cardioprotective agent. Evid Based Complement Alternat Med. 2012:7164592012. View Article : Google Scholar : PubMed/NCBI | |
Jiang FL, Leo S, Wang XG, Li H, Gong LY, Kuang Y and Xu XF: Effect of tanshinone IIA on cardiomyocyte hypertrophy and apoptosis in spontaneously hypertensive rats. Exp Ther Med. 6:1517–1521. 2013.PubMed/NCBI | |
Jin HJ and Li CG: Tanshinone IIA and cryptotanshinone prevent mitochondrial dysfunction in hypoxia-induced H9c2 cells: Association to mitochondrial ROS, intracellular nitric oxide and calcium levels. Evid Based Complement Alternat Med. 2013:6106942013. View Article : Google Scholar : PubMed/NCBI | |
Jin HJ, Xie XL, Ye JM and Li CG: Tanshinoneiia and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells. PLoS One. 8:e517202013. View Article : Google Scholar : PubMed/NCBI | |
Jung JH, Kwon TR, Jeong SJ, Kim EO, Sohn EJ, Yun M and Kim SH: Apoptosis induced by tanshinone IIA and cryptotanshinone is mediated by distinct JAK/STAT3/5 and SHP1/2 signaling in chronic myeloid leukemia K562 cells. Evid Based Complement Alternat Med. 2013:8056392013. View Article : Google Scholar : PubMed/NCBI | |
Liu JJ, Lin DJ, Liu PQ, Huang M, Li XD and Huang RW: Induction of apoptosis and inhibition of cell adhesive and invasive effects by tanshinone IIA in acute promyelocytic leukemia cells in vitro. J Biomed Sci. 13:813–823. 2006. View Article : Google Scholar : PubMed/NCBI | |
Wang JF, Feng JG, Han J, Zhang BB and Mao WM: The molecular mechanisms of tanshinone IIA on the apoptosis and arrest of human esophageal carcinoma cells. Biomed Res Int. 2014:5827302014.PubMed/NCBI | |
Tseng PY, Lu WC, Hsieh MJ, Chien SY and Chen MK: Tanshinone IIA induces apoptosis in human oral cancer KB cells through a mitochondria-dependent pathway. Biomed Res Int. 2014:5405162014. View Article : Google Scholar : PubMed/NCBI | |
Shan YF, Shen X, Xie YK, Chen JC, Shi HQ, Yu ZP, Song QT, Zhou MT and Zhang QY: Inhibitory effects of tanshinone II-a on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol Sin. 30:1537–1542. 2009. View Article : Google Scholar : PubMed/NCBI | |
Su CC: Tanshinone IIA potentiates the efficacy of 5-FU in colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II. Exp Ther Med. 3:555–559. 2012.PubMed/NCBI | |
Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, de Celis-Carrillo R, del Toro-Arreola S, Castellanos-Esparza YC and Bravo-Cuellar A: Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing nf-kappa B and decreased cell senescence. BMC Cancer. 11:4832011. View Article : Google Scholar : PubMed/NCBI | |
Liu T, Liu D, Liu J, Song JT, Gao SL, Li H, Hu LH and Liu BR: Effect of NF-κB inhibitors on the chemotherapy-induced apoptosis of the colon cancer cell line HT-29. Exp Ther Med. 4:716–722. 2012.PubMed/NCBI | |
Wang S, Liu Z, Wang L and Zhang X: NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 6:327–334. 2009. View Article : Google Scholar : PubMed/NCBI |