Paraptosis and NF-κB activation are associated with protopanaxadiol-induced cancer chemoprevention

BMC Complementary and Alternative Medicine

Chun-Su Yuan¹  Wei Du²  Tong-Chuan He³  Tyler D Calway⁴  Chunhao Yu⁴  Zhiyu Zhang⁴  Xiao-Dong Wen⁴  Binghui Li²  Chong-Zhi Wang⁴ 

[1] Tang Center for Herbal Medicine Research, and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL, 60637, USA;Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA;Department of Surgery, University of Chicago, Chicago, IL, USA;Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA

关键词: Cancer chemoprevention;    Antioxidant;    Mitochondrial swelling;    Cytoplasmic vacuoles;    Paraptosis;    PPD;    Protopanaxadiol;    Ginseng;   

Others  :  1231298
DOI  :  10.1186/1472-6882-13-2

 received in 2012-10-04, accepted in 2012-12-19,  发布年份 2013

【 摘 要 】

Background

Protopanaxadiol (PPD) is a triterpenoid that can be prepared from steamed ginseng. PPD possesses anticancer potential via caspase-dependent apoptosis. Whether paraptosis, a type of the caspase-independent cell death, is also induced by PPD has not been evaluated.

Methods

Cell death, the cell cycle and intracellular reactive oxygen species (ROS) were analyzed by flow cytometry after staining with annexin V/PI, PI/RNase or H2DCFDA. We observed morphological changes by crystal violet staining assay. Mitochondrial swelling was measured by ultraviolet–visible spectrophotometry. The activation of NF-κB was measured by luciferase reporter assay.

Results

At comparable concentrations of 5-fluorouracil, PPD induced more cell death in human colorectal cancer cell lines HCT-116 and SW-480. We demonstrated that PPD induced paraptosis in these cancer cells. PPD treatment significantly increased the percentage of cancer cells with cytoplasmic vacuoles. After the cells were treated with PPD and cycloheximides, cytoplasmic vacuole generation was inhibited. The paraptotic induction effect of PPD was also supported by the results of the mitochondrial swelling assay. PPD induced ROS production in cancer cells, which activated the NF-κB pathway. Blockage of ROS by NAC or PS-1145 inhibited the activation of NF-κB signaling.

Conclusions

PPD induces colorectal cancer cell death in part by induction of paraptosis. The anticancer activity of PPD may be enhanced by antioxidants such as green tea, which also inhibit the activation of NF-κB signaling.

【 授权许可】

   
2013 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Wood CG: Multimodal approaches in the management of locally advanced and metastatic renal cell carcinoma: combining surgery and systemic therapies to improve patient outcome. Clin Cancer Res 2007, 13(2 Pt 2):697s-702s.
• [2]Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007, 297(3):267-277.
• [3]Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM: Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011, 305(22):2335-2342.
• [4]Wang CZ, Calway T, Yuan CS: Herbal medicines as adjuvants for cancer therapeutics. Am J Chin Med 2012, 40(4):657-669.
• [5]Bougnoux P, Hajjaji N, Maheo K, Couet C, Chevalier S: Fatty acids and breast cancer: sensitization to treatments and prevention of metastatic re-growth. Prog Lipid Res 2010, 49(1):76-86.
• [6]Lee KH: Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod 2010, 73(3):500-516.
• [7]Qi LW, Wang CZ, Yuan CS: American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol 2010, 80(7):947-954.
• [8]Xu Z, Chen X, Zhong Z, Chen L, Wang Y: Ganoderma lucidum polysaccharides: immunomodulation and potential anti-tumor activities. Am J Chin Med 2011, 39(1):15-27.
• [9]Yun TK: Panax ginseng–a non-organ-specific cancer preventive? Lancet Oncol 2001, 2(1):49-55.
• [10]Yun TK, Zheng S, Choi SY, Cai SR, Lee YS, Liu XY, Cho KJ, Park KY: Non-organ-specific preventive effect of long-term administration of Korean red ginseng extract on incidence of human cancers. J Med Food 2010, 13(3):489-494.
• [11]Li XL, Wang CZ, Mehendale SR, Sun S, Wang Q, Yuan CS: Panaxadiol, a purified ginseng component, enhances the anti-cancer effects of 5-fluorouracil in human colorectal cancer cells. Cancer Chemother Pharmacol 2009, 64(6):1097-1104.
• [12]Fishbein AB, Wang CZ, Li XL, Mehendale SR, Sun S, Aung HH, Yuan CS: Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: comparison between white and red ginseng. Arch Pharm Res 2009, 32(4):505-513.
• [13]Hwang JW, Oh JH, Yoo HS, Lee YW, Cho CK, Kwon KR, Yoon JH, Park J, Her S, Lee ZW, Jang IS, Choi JS: Mountain ginseng extract exhibits anti-lung cancer activity by inhibiting the nuclear translocation of NF-kappaB. Am J Chin Med 2012, 40(1):187-202.
• [14]Wang CZ, Aung HH, Ni M, Wu JA, Tong R, Wicks S, He TC, Yuan CS: Red American ginseng: ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots. Planta Med 2007, 73(7):669-674.
• [15]Sun S, Qi LW, Du GJ, Mehendale SR, Wang CZ, Yuan CS: Red notoginseng: higher ginsenoside content and stronger anticancer potential than Asian and American ginseng. Food Chem 2011, 125(4):1299-1305.
• [16]Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS, Du W: Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett 2011, 301(2):185-192.
• [17]Wang CZ, Zhang B, Song WX, Wang A, Ni M, Luo X, Aung HH, Xie JT, Tong R, He TC, Yuan CS: Steamed American ginseng berry: ginsenoside analyses and anticancer activities. J Agric Food Chem 2006, 54(26):9936-9942.
• [18]Du GJ, Dai Q, Williams S, Wang CZ, Yuan CS: Synthesis of protopanaxadiol derivatives and evaluation of their anticancer activities. Anticancer Drugs 2011, 22(1):35-45.
• [19]Chen TS, Wang XP, Sun L, Wang LX, Xing D, Mok M: Taxol induces caspase-independent cytoplasmic vacuolization and cell death through endoplasmic reticulum (ER) swelling in ASTC-a-1 cells. Cancer Lett 2008, 270(1):164-172.
• [20]Greenlee H, Gammon MD, Abrahamson PE, Gaudet MM, Terry MB, Hershman DL, Desai M, Teitelbaum SL, Neugut AI, Jacobson JS: Prevalence and predictors of antioxidant supplement use during breast cancer treatment: the Long Island Breast Cancer Study Project. Cancer 2009, 115(14):3271-3282.
• [21]Myung SK, Kim Y, Ju W, Choi HJ, Bae WK: Effects of antioxidant supplements on cancer prevention: meta-analysis of randomized controlled trials. Ann Oncol 2010, 21(1):166-179.
• [22]Fernandez-Gomez FJ, Galindo MF, Gomez-Lazaro M, Gonzalez-Garcia C, Cena V, Aguirre N, Jordan J: Involvement of mitochondrial potential and calcium buffering capacity in minocycline cytoprotective actions. Neuroscience 2005, 133(4):959-967.
• [23]Qi LW, Wang CZ, Yuan CS: Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry 2011, 72(8):689-699.
• [24]Qi LW, Wang CZ, Yuan CS: Isolation and analysis of ginseng: advances and challenges. Nat Prod Rep 2011, 28(3):467-495.
• [25]Wang CZ, Kim KE, Du GJ, Qi LW, Wen XD, Li P, Bauer BA, Bissonnette MB, Musch MW, Chang EB, Yuan CS: Ultra-performance liquid chromatography and time-of-flight mass spectrometry analysis of ginsenoside metabolites in human plasma. Am J Chin Med 2011, 39(6):1161-1171.
• [26]Wang HY, Qi LW, Wang CZ, Li P: Bioactivity enhancement of herbal supplements by intestinal microbiota focusing on ginsenosides. Am J Chin Med 2011, 39(6):1103-1115.
• [27]Din FV, Dunlop MG, Stark LA: Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 2004, 91(2):381-388.
• [28]Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003, 3(5):330-338.
• [29]Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000, 355(9209):1041-1047.
• [30]Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000, 18(1):136-147.
• [31]Choudhary B, Hanski ML, Zeitz M, Hanski C: Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment. Cancer Lett 2012, 320(1):56-64.
• [32]Du GJ, Wang CZ, Qi LW, Zhang ZY, Calway T, He TC, Du W, Yuan CS: The synergistic apoptotic interaction of panaxadiol and epigallocatechin gallate in human colorectal cancer cells. Phytother Res 2012., 26In press