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Inhibition of NF-κB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel

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Abstract

Ginsenoside Rg3, the main constituent isolated from Panax ginseng, has been of interest for use as a cancer preventive or therapeutic agent. We investigated here whether Rg3 can inhibit the activity of NF-κB, a key transcriptional factor constitutively activated in colon cancer that confers cancer cell resistance to chemotherapeutic agents. To investigate whether RG3 can suppress activation of NF-κB, and thus inhibit cancer cell growth, we examined the susceptibility of colon cancer cells (SW620 and HCT116) to treatment with Rg3 (25, 50, 75, 100 μM) and RG3-induced activation of NF-κB. RG3 dose-dependently inhibited cancer cell growth through induction of apoptosis and decreased NF-κB activity. In a further study of compounds in colon cancer, we used half of the IC50 dose, values in combined treatments of Rg3 (50 μM) with conventional agents — docetaxel (5 nM), paclitaxel (10 nM) cisplatin (10 μM) and doxorubicin (2 μM). Compared to treatment with Rg3 or chemotherapy alone, combined treatment was more effective (i.e., there were synergistic effects) in the inhibition of cancer cell growth and induction of apoptosis and these effects were accompanied by significant inhibition of NF-κB activity. NF-κB target gene expression of apoptotic cell death proteins (Bax, caspase-3, caspase-9) was significantly enhanced, but the expression of anti-apoptotic genes and cell proliferation marker genes (Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), Cox-2, c-Fos, c-Jun and cyclin D1) was significantly inhibited by the combined treatment compared to Rg3 or docetaxel alone. These results indicate that ginsenoside Rg3 inhibits NF-κB, and enhances the susceptibility of colon cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer or adjuvant anti-cancer agent.

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References

  • Amer, A. B. and Baltimore, D., An essential role for NF-κB in preventing TNF-α induced cell death. Science, 274, 782–784 (1996).

    Article  Google Scholar 

  • Ban, J. O., Yuk, D. Y., Woo, K. S., Kim, T. M., Lee, U. S., Jeong, H. S., Kim, D. J., Chung, Y. B., Hwang, B. Y., Oh, K. W., and Hong, J. T., Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells. J. Pharmacol. Sci., 104, 374–383 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Barkett, M. and Gilmore, T. D., Control of apoptosis by Rel/NF-κB transcription factors. Oncogene, 18, 6910–6924 (1999)

    Article  PubMed  CAS  Google Scholar 

  • Bednarski, B. K., Ding, X., Coombe, K., Baldwin, A. S, Kim, H. J., Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicin. Mol. Cancer. Ther., 7, 1827–1835 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Bours, V., Dejardin, E., Goujon-Letawe, F., Merville, M. P., and Castronovo, V., The NF-kappa B transcription factor and cancer: high expression of NF-kappa B- and I kappa B related proteins in tumor cell lines. Biochem. Pharmacol., 47, 145–149 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Chuang, S. E., Yeh, P. Y., and Lu, Y. S., Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Biochem. Pharmacol., 63, 1709–1716 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Cortes, J. E. and Pazdur, R., Docetaxel. J. Clin. Oncol., 13, 2643–2655 (1995).

    PubMed  CAS  Google Scholar 

  • Cusack, J. C. Jr., Liu, R., and Baldwin, A. S. Jr., Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation. Cancer Res., 60, 2323–2330 (2000).

    PubMed  CAS  Google Scholar 

  • Diaz-Rubio, E., New chemotherapeutic advances in pancreatic, colorectal, and gastric cancers. Oncologist., 9, 282–294 (2004)

    Article  PubMed  CAS  Google Scholar 

  • Dong, Q. G., Sclabas, G. M., and Fujioka, S., The function of multiple IkappaB: NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene, 21, 6510–6519 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Ferraresi, V., Milella, M., Vaccaro, A., D’Ottavio, A. M., Papaldo, P., Nisticò, C., Thorel, M. F., Marsella, A., Carpino, A., Giannarelli, D., Terzoli, E., and Cognetti, F., Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients: a phase II study. Am. J. Clin. Oncol., 23, 132–139 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Fossella, F. V., DeVore, R., Kerr, R. N., Crawford, J., Natale, R. R., Dunphy, F., Kalman, L., Miller, V., Lee, J. S., Moore, M., Gandara, D., Karp, D., Vokes, E., Kris, M., Kim, Y., Gamza, F., and Hammershaimb, L., Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J. Clin. Oncol., 18, 2354–2362 (2000).

    PubMed  CAS  Google Scholar 

  • Garg, A. and Aggarwal, B. B., Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia, 16, 1053–1068 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., and Egan, L. J., IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 118, 285–296 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Helms, S., Cancer prevention and therapeutics: Panax ginseng. Altern. Med. Rev., 9, 259–274 (2004).

    PubMed  Google Scholar 

  • Huang, Y., Johnson, K. R., Norris, J. S., and Fan, W., Nuclear factor-kappaB/ IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells. Cancer Res., 60, 4426–4432 (2000).

    PubMed  CAS  Google Scholar 

  • Kasibhatla, S., Brunner, T., Genestier, L., Echeverri, F., Mahboubi, A., and Green, D. R., DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1. Mol. Cell., 1, 543–551 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Keum, Y. S., Han, S. S., Chun, K. S., Park, K. K., Park, J. H., Lee, S. K., and Surh, Y. J., Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-kappaB activation and tumor promotion. Mutat. Res., 524, 75–85 (2003).

    Google Scholar 

  • Lee, S. H., Lee, C. W., Lee, J. W., Choi, M. S., Son, D. J., Chung, Y. B., Lee, C. K., Oh, K. W., Moon, D. C., Kwon, B. M., and Hong, J. T., Induction of apoptotic cell death by 2′-hydroxycinnamaldehyde is involved with ERK-dependent inactivation of NF-kappaB in TNF-alpha-treated SW620 colon cancer cells. Biochem. Pharmacol., 70, 1147–1157 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Li, Y., Ellis, K. L., and Ali, S., Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas., 28, 90–95 (2004).

    Article  Google Scholar 

  • Lin, Z. P., Boller, Y. C., Amer, S. M., Russell, R. L., Pacelli, K. A., Patierno, S. R., and Kennedy, K. A., Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-κB activation in drug resistance. Cancer Res., 58, 3059–3065 (1998).

    PubMed  CAS  Google Scholar 

  • Lind, D. S., Hochwald, S. N., Malaty, J., Rekkas, S., Hebig, P., Mishra, G., Moldawer, L. L., Copeland, E. M. 3rd., and MacKay, S., Nuclear factor-kappa B is upregulated in colorectal cancer. Surgery, 130, 363–369 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Mabuchi, S., Ohmichi, M., Nishio, Y., Hayasaka, T., Kimura, A., Ohta, T., Kawagoe, J., Takahashi, K., Yada-Hashimoto, N., Seino-Noda, H., Sakata, M., Motoyama, T., Kurachi, H., Testa, J. R., Tasaka, K., and Murata, Y., Inhibition of inhibitor of nuclear factor-kappaB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Clin. Cancer Res., 10, 7645–7654 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Marianneau, P., Cardona, A., Edelman, L., Deubel, V., and Despres, P., Dengue virus replication in human hepatoma cells activates NF-κB which in turn induces apoptotic cell death. J. Virol., 71, 3244–3249 (1997).

    PubMed  CAS  Google Scholar 

  • Millikan, R., Baez, L., Banerjee, T., Wade, J., Edwards, K., Winn, R., Smith, T. L., and Logothetis, C., Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol. Oncol., 6, 111–115 (2001).

    Article  PubMed  Google Scholar 

  • Okada, S., Sakata, Y., Matsuno, S., Kurihara, M., Sasaki, Y., Ohashi, Y., and Taguchi, T., Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. Br. J. Cancer, 80, 438–443 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Oyaizu, H., Adachi, Y., and Okumura, T., Proteasome inhibitor 1 enhances paclitaxel-induced apoptosis in human lung adenocarcinoma cell line. Oncol. Rep., 8, 825–829 (2001).

    PubMed  CAS  Google Scholar 

  • Perkins, N. D., The Rel/NF-κB family: friend and foe. Trends. Biochem. Sci., 25, 434–440 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature, 431, 461–466 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Qin, Z. H., Wang, Y., Nakai, M., and Chase, T. N., Nuclear factor-κB contributes to excitotoxin-induced apoptosis in rat striatum. Mol. Pharmacol., 53, 33–42 (1998).

    PubMed  CAS  Google Scholar 

  • Ryan, D. P., Kulke, M. H., Fuchs, C. S., Grossbard, M. L., Grossman, S. R., Morgan, J. A., Earle, C. C., Shivdasani, R., Kim, H., Mayer, R. J., and Clark, J. W., A Phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer, 94, 97–103 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Schneider, A., Martin-Villalba, A., Weih, F., Vogel, J., Wirth, T., and Schwaninger, M., NF-κB is activated and promotes cell death in focal cerebral ischemia. Nat. Med., 5, 554–559 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Singh, S. and Bhat, M. K., Carboplatin induces apoptotic cell death through downregulation of constitutively active nuclear factor-kappaB in human HPV-18 E6-positive HEp-2 cells. Biochem. Biophys. Res. Commun., 318, 346–353 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Son, D. J., Park, M. H., Chae, S. J., Moon, S. O., Lee, J. W., Song, H. S., Moon, D. C., Kang, S. S., Kwon, Y. E., and Hong, J. T. Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor kappaB. Mol. Cancer Ther., 6, 675–683 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Strasser, F., Hailemariam, S., Hauser, M., and Pestalozzi, B. C., A 53-year-old patient with unilateral pulmonary infiltrates following a single dose of mitomycin, vindesine and cisplatin chemotherapy for non-small-cell lung cancer. Respiration, 66, 562–572 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Suh, Y., Afaq, F., Johnson, J. J., and Mukhtar, H., A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-{kappa}B signaling pathways. Carcinogenesis, Epub ahead of print, (2008)

  • Tedesco, K. L., Thor, A. D., Johnson, D. H., Shyr, Y., Blum, K. A., Goldstein, L. J., Gradishar, W. J., Nicholson, B. P., Merkel, D. E., Murrey, D., Edgerton, S., and Sledge, G. W. Jr., Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial. J. Clin. Oncol., 22, 1071–1077 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Tyagi, A. K., Singh, R. P., Agarwal, C., Chan, D. C., and Agarwal, R., Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin. Cancer Res., 8, 3512–9 (2002).

    PubMed  CAS  Google Scholar 

  • Van, Antwerp. D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M., Suppression of TNF-α-induced apoptosis by NF-κB. Science., 274, 787–789 (1996).

    Article  PubMed  Google Scholar 

  • Waddick, K. G., and Uckun, F. M., Innovative treatment programs against cancer: II. Nuclear factor-κB (NF-κB) as a molecular target. Biochem. Pharmacol., 57, 9–17 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Wang, C. Y., Cusack, J. C., Liu, R., and Baldwin, A. S. Jr., Control of inducible chemoresistance: enhanced antitumor therapy through increased apoptosis by inhibition of NF-κB. Nat. Med., 5, 412–417 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Wang, C. Y., Mayo, M. W., and Baldwin, A. S. Jr., TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science., 274, 784–787 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Weldon, C. B., Burow, M. E., Rolfe, K. W., Clayton, J. L., Jaffe, B. M., and Beckman B. S., NF-kappa B-mediated chemoresistance in breast cancer cells. Surgery,130, 143–150 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Xiuli, W., Yan, W., Wenqian, Z., and Yixuan, Z., Fungal biotransformation of ginsenoside Rg3. Wei Sheng Wu Xue Bao, 48, 1181–5 (2008).

    PubMed  Google Scholar 

  • Yun, T. K., Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutat. Res., 523–524, 63–74 (2003).

    PubMed  Google Scholar 

  • Zhang, H., Morisaki, T., and Nakahara, C., PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1. Oncogene, 22, 2088–2096 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Zhao, Y., Wang, W., Han, L., Rayburn, E. R., Hill, D. L., Wang, H., and Zhang, R., Isolation, structural determination, and evaluation of the biological activity of 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol [20(S)-25-OCH3-PPD], a novel natural product from Panax notoginseng. Med. Chem., 3, 51–60 (2007).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. College of Pharmacy and CBITRC, Chungbuk National University, Cheongju, 361-763, Korea

    Sun Mi Kim, So Yong Lee, Dong Yeon Yuk, Dong Cheul Moon, Youngsoo Kim, Sang Bae Han, Ki-Wan Oh & Jin Tae Hong

  2. Medical Research Center, Chungbuk National University, Cheongju, 361-763, Korea

    So Yong Lee, Dong Yeon Yuk, Sang Sook Choi, Sang Bae Han & Jin Tae Hong

  3. Food and Drug Administration, Seoul, 122-020, Korea

    Sun Mi Kim

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  1. Sun Mi Kim
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Correspondence to Jin Tae Hong.

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Kim, S.M., Lee, S.Y., Yuk, D.Y. et al. Inhibition of NF-κB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. Arch. Pharm. Res. 32, 755–765 (2009). https://doi.org/10.1007/s12272-009-1515-4

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