Inactivation of Nuclear Factor κB by Soy Isoflavone Genistein Contributes to Increased Apoptosis Induced by Chemotherapeutic Agents in Human Cancer Cells

Cancer Research - Tập 65 Số 15 - Trang 6934-6942 - 2005
Yiwei Li1, Fakhara Ahmed1, Shadan Ali2, Philip A. Philip2, Ömer Küçük2, Fazlul H. Sarkar1
11Pathology and Departments of
22Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

Tóm tắt

Abstract Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor κB (NF-κB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-κB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-κB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 μmol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 μmol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-κB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-κB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-κB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-κB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.

Từ khóa


Tài liệu tham khảo

Bredel M. Anticancer drug resistance in primary human brain tumors. Brain Res Brain Res Rev 2001; 35: 161–204.

El Rayes BF, Zalupski MM, Shields AF, et al. Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer. J Clin Oncol 2003; 21: 2920–5.

Ganjoo KN, Gordon MS, Sandler AB, et al. A phase I study of weekly gemcitabine and docetaxel in patients with advanced cancer: a Hoosier Oncology Group Study. Oncology 2002; 62: 299–304.

Hortobagyi GN. Recent progress in the clinical development of docetaxel (Taxotere). Semin Oncol 1999; 26: 32–6.

Jacobs AD. Gemcitabine-based therapy in pancreas cancer: gemcitabine-docetaxel and other novel combinations. Cancer 2002; 95: 923–7.

Lenzi R, Yalcin S, Evans DB, Abbruzzese JL. Phase II study of docetaxel in patients with pancreatic cancer previously untreated with cytotoxic chemotherapy. Cancer Invest 2002; 20: 464–72.

Colon-Otero G, Niedringhaus RD, Hillman SH, et al. A phase II trial of edatrexate, vinblastine, Adriamycin, cisplastin, and filgrastim (EVAC/G-CSF) in patients with non-small-cell carcinoma of the lungs: a North Central Cancer Treatment Group Trial. Am J Clin Oncol 2001; 24: 551–5.

Wagenaar HC, Pecorelli S, Vergote I, et al. Phase II study of a combination of cyclophosphamide, Adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer. Eur J Gynaecol Oncol 2001; 22: 187–93.

Kurtz JE, Negrier S, Husseini F, et al. A phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer. Hepatogastroenterology 2003; 50: 567–70.

Philip PA, Zalupski MM, Vaitkevicius VK, et al. Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 2001; 92: 569–77.

Cascinu S, Gasparini G, Catalano V, et al. A phase I-II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann Oncol 1999; 10: 1377–9.

Evans TR, Lofts FJ, Mansi JL, Glees JP, Dalgleish AG, Knight MJ. A phase II study of continuous-infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer. Br J Cancer 1996; 73: 1260–4.

Bian X, McAllister-Lucas LM, Shao F, et al. NF-κ B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J Biol Chem 2001; 276: 48921–9.

Chuang SE, Yeh PY, Lu YS, et al. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-κB (NF-κB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Biochem Pharmacol 2002; 63: 1709–16.

Yeh PY, Chuang SE, Yeh KH, Song YC, Ea CK, Cheng AL. Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF-κB activation. Biochem Pharmacol 2002; 63: 1423–30.

Lin ZP, Boller YC, Amer SM, et al. Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-κB activation in drug resistance. Cancer Res 1998; 58: 3059–65.

Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr 1995; 125: 777–83S.

Davis JN, Singh B, Bhuiyan M, Sarkar FH. Genistein-induced up-regulation of p21WAF1, down-regulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 1998; 32: 123–31.

Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 1999; 18: 3166–72.

Li Y, Sarkar FH. Gene expression profiles of genistein-treated PC3 prostate cancer cells. J Nutr 2002; 132: 3623–31.

Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-κ B activation in prostate cancer cells. Nutr Cancer 1999; 35: 167–74.

Li Y, Sarkar FH. Inhibition of nuclear factor κB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 2002; 8: 2369–77.

Li Y, Che M, Bhagat S, et al. Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia 2004; 6: 354–63.

American Cancer Society. Cancer Facts and Figures 2004. Atlanta: American Cancer Society, Inc; 2004.

Verweij J, de Jonge MJ. Achievements and future of chemotherapy. Eur J Cancer 2000; 36: 1479–87.

Liem AA, Chamberlain MP, Wolf CR, Thompson AM. The role of signal transduction in cancer treatment and drug resistance. Eur J Surg Oncol 2002; 28: 679–84.

Yeh PY, Chuang SE, Yeh KH, Song YC, Cheng AL. Involvement of nuclear transcription factor-κ B in low-dose doxorubicin-induced drug resistance of cervical carcinoma cells. Biochem Pharmacol 2003; 66: 25–33.

Chawla-Sarkar M, Bauer JA, Lupica JA, et al. Suppression of NF-κ B survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL. J Biol Chem 2003; 278: 39461–9.

Han SY, Choung SY, Paik IS, et al. Activation of NF-κB determines the sensitivity of human colon cancer cells to TNFα-induced apoptosis. Biol Pharm Bull 2000; 23: 420–6.

Li Y, Ellis KL, Ali S, et al. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-κB in BxPC-3 pancreatic cancer cell line. Pancreas 2004; 28: e90–5.

Ganansia-Leymarie V, Bischoff P, Bergerat JP, Holl V. Signal transduction pathways of taxane-induced apoptosis. Curr Med Chem Anti-Canc Agents 2003; 3: 291–306.

Azuma M, Tamatani T, Ashida Y, Takashima R, Harada K, Sato M. Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-κB-suppressed pathway. Oral Oncol 2003; 39: 282–9.

Takeuchi K, Ito F. Suppression of Adriamycin-induced apoptosis by sustained activation of the phosphatidylinositol-3′-OH kinase-Akt pathway. J Biol Chem 2004; 279: 892–900.

Huang Z. Bcl-2 family proteins as targets for anticancer drug design. Oncogene 2000; 19: 6627–31.

Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999; 39: 295–312.

Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003; 3: 46–54.

Su SJ, Chow NH, Kung ML, Hung TC, Chang KL. Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL down-regulation, and Cdc2 kinase activity. Nutr Cancer 2003; 45: 113–23.

Suzuki K, Koike H, Matsui H, et al. Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer 2002; 99: 846–52.

Viatour P, tires-Alj M, Chariot A, et al. NF-κ B2/p100 induces Bcl-2 expression. Leukemia 2003; 17: 1349–56.

Mori N, Fujii M, Cheng G, et al. Human T-cell leukemia virus type I tax protein induces the expression of anti-apoptotic gene Bcl-xL in human T-cells through nuclear factor-κB and c-AMP responsive element binding protein pathways. Virus Genes 2001; 22: 279–87.

Otaki M, Hatano M, Kobayashi K, Ogasawara T, Kuriyama T, Tokuhisa T. Cell cycle-dependent regulation of TIAP/m-survivin expression. Biochim Biophys Acta 2000; 1493: 188–94.

To H, Ohdo S, Shin M, et al. Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats. J Pharm Pharmacol 2003; 55: 803–10.

Ravdin PM, Burris HA III, Cook G, et al. Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 1995; 13: 2879–85.

Thông tin
Thông tin xuất bản

Cancer Research

Tập 65 Số 15

6934-6942

Thông tin tác giả