Browse > Article
http://dx.doi.org/10.1016/j.jgr.2019.12.007

Anti-tumor activities of Panax quinquefolius saponins and potential biomarkers in prostate cancer  

He, Shan (Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Vienna General Hospital, Medical University of Vienna)
Lyu, Fangqiao (Department of Cell Biology, School of Basic Medicine, Capital Medical University)
Lou, Lixia (The Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine)
Liu, Lu (Beijing Hospital of Traditional Chinese Medicine, Capital Medical University)
Li, Songlin (Department of Pharmaceutical Analysis and Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine and Jiangsu Branch of China Academy of Chinese Medical Sciences)
Jakowitsch, Johannes (Department of Internal Medicine, Vienna General Hospital, Medical University of Vienna)
Ma, Yan (Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Vienna General Hospital, Medical University of Vienna)
Publication Information
Journal of Ginseng Research / v.45, no.2, 2021 , pp. 273-286 More about this Journal
Abstract
Background: Prostate carcinoma is the second most common cancer among men worldwide. Developing new therapeutic approaches and diagnostic biomarkers for prostate cancer (PC) is a significant need. The Chinese herbal medicine Panax quinquefolius saponins (PQS) have been reported to show anti-tumor effects. We hypothesized that PQS exhibits anti-cancer activity in human PC cells and we aimed to search for novel biomarkers allowing early diagnosis of PC. Methods: We used the human PC cell line DU145 and the prostate epithelial cell line PNT2 to perform cell viability assays, flow cytometric analysis of the cell cycle, and FACS-based apoptosis assays. Microarray-based gene expression analysis was used to display specific gene expression patterns and to search for novel biomarkers. Western blot and quantitative real-time PCR were performed to demonstrate the expression levels of multiple cancer-related genes. Results: Our data showed that PQS inhibited the viability of DU145 cells and induced cell cycle arrest at the G1 phase. A significant decrease in DU145 cell invasion and migration were observed after 24 h treatment by PQS. PQS up-regulated the expression levels of p21, p53, TMEM79, ACOXL, ETV5, and SPINT1 while it down-regulated the expression levels of bcl2, STAT3, FANCD2, DRD2, and TMPRSS2. Conclusion: PQS promoted cells apoptosis and inhibited the proliferation of DU145 cells, which suggests that PQS may be effective for treating PC. TMEM79 and ACOXL were expressed significantly higher in PNT2 than in DU145 cells and could be novel biomarker candidates for PC diagnosis.
Keywords
Chinese medicinal herbs; Panax quinquefolius; Potential biomarkers; Prostate cancer cells; saponins;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 O'Hurley G, Busch C, Fagerberg L, Hallstrom BM, Stadler C, Tolf A, et al. Analysis of the human prostate-specific proteome defined by transcriptomics and antibody-based profiling identifies TMEM79 and ACOXL as two putative, diagnostic markers in prostate cancer. PLoS One 2015;10:e0133449.   DOI
2 Scholey A, Ossoukhova A, Owen L, Ibarra A, Pipingas A, He K, et al. Effects of American ginseng (Panax quinquefolius) on neurocognitive function: an acute, randomised, double-blind, placebo-controlled, crossover study. Psychopharmacology (Berl) 2010;212:345-56.   DOI
3 Jia L, Zhao Y. Current evaluation of the millennium phytomedicine-ginseng (I): etymology, pharmacognosy, phytochemistry, market and regulations. Curr Med Chem 2009;16:2475-84.   DOI
4 Petros AM, Gunasekera A, Xu N, Olejniczak ET, Fesik SW. Defining the p53 DNA-binding domain/Bcl-x(L)-binding interface using NMR. FEBS Lett 2004;559:171-4.   DOI
5 Suzuki Y, Kondo Y, Himeno S, Nemoto K, Akimoto M, Imura N. Role of antioxidant systems in human androgen-independent prostate cancer cells. Prostate 2000;43:144-9.   DOI
6 Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nature Reviews Cancer 2001;1(1):34-45.   DOI
7 Kim SJ, Kim AK. Anti-breast cancer activity of fine black ginseng (Panax ginseng Meyer) and ginsenoside Rg5. J Ginseng Res 2015;39:125-34.   DOI
8 Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 1994;54:2577-81.
9 Zhang T, Zhu J, George DJ, Armstrong AJ. Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer. Expert Opin Pharmacother 2015;16:473-85.   DOI
10 de la Taille A, Hayek OR, Burchardt M, Burchardt T, Katz AE. Role of herbal compounds (PC-SPES) in hormone-refractory prostate cancer: two case reports. J Altern Complement Med 2000;6:449-51.   DOI
11 Zhang Z, Du GJ, Wang CZ, Wen XD, Calway T, Li Z, et al. Compound K, a ginsenoside metabolite, inhibits colon cancer growth via multiple pathways including p53-p21 interactions. Int J Mol Sci 2013;14:2980-95.   DOI
12 Chen P, Luthria D, Harrington Pde B, Harnly JM. Discrimination among Panax species using spectral fingerprinting. J AOAC Int 2011;94:1411-21.   DOI
13 Paur I, Lilleby W, Bohn SK, Hulander E, Klein W, Vlatkovic L, et al. Tomato-based randomized controlled trial in prostate cancer patients: effect on PSA. Clin Nutr 2017;36:672-9.   DOI
14 Harrison MR, Wong TZ, Armstrong AJ, George DJ. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res 2013;5:1-14.   DOI
15 Park JY, Choi P, Kim HK, Kang KS, Ham J. Increase in apoptotic effect of Panax ginseng by microwave processing in human prostate cancer cells: in vitro and in vivo studies. J Ginseng Res 2016;40:62-7.   DOI
16 Wilt TJ, Ishani A, Rutks I, MacDonald R. Phytotherapy for benign prostatic hyperplasia. Public Health Nutr 2000;3:459-72.   DOI
17 Yoo JH, Kwon HC, Kim YJ, Park JH, Yang HO. KG-135, enriched with selected ginsenosides, inhibits the proliferation of human prostate cancer cells in culture and inhibits xenograft growth in athymic mice. Cancer Lett 2010;289:99-110.   DOI
18 Badrising S, van der Noort V, van Oort IM, van den Berg HP, Los M, Hamberg P, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014;120:968-75.   DOI
19 Domnick M, Domnick M, Wiebelitz KR, Beer AM. Evaluation of the effectiveness of a multimodal complementary medicine program for improving the quality of life of cancer patients during adjuvant radiotherapy and/or chemotherapy or outpatient Aftercare. Oncology 2017;93:83-91.   DOI
20 van Die MD, Williams SG, Emery J, Bone KM, Taylor JM, Lusk E, et al. A placebo-controlled double-blinded randomized pilot study of combination phytotherapy in biochemically recurrent prostate cancer. Prostate 2017;77:765-75.   DOI
21 Hirata H, Hinoda Y, Shahryari V, Deng G, Tanaka Y, Tabatabai ZL, et al. Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells. Br J Cancer 2014;110:1645-54.   DOI
22 Cao B, Bray F, Beltran-Sanchez H, Ginsburg O, Soneji S, Soerjomataram I. Benchmarking life expectancy and cancer mortality: global comparison with cardiovascular disease 1981-2010. BMJ 2017;357:j2765.
23 Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2017;67:7-30. 2017.   DOI
24 Mottet N, Bellmunt J, Briers E, Bolla M, Cornford P, De Santis M, Henry A, Joniau S, Lam T, Mason MD, et al. EAU - ESTRO - SIOG guidelines on prostate cancer. European Association of Urology; 2016. 2016.
25 Chen S WZ, Huang Y, O'Barr SA, Wong RA, Yeung S, Chow MS. Ginseng and anticancer drug combination to improve cancer. Evidence-Based Complementary and Alternative Medicine 2014;2014.
26 Chen P, Harnly JM, Harrington Pde B. Flow injection mass spectroscopic fingerprinting and multivariate analysis for differentiation of three Panax species. J AOAC Int 2011;94:90-9.   DOI
27 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.   DOI
28 Huang KC. The pharmacology of Chinese herbs. CRC Press LLC; 1999.
29 Tang YC, Zhang Y, Zhou J, Zhi Q, Wu MY, Gong FR, et al. Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int J Oncol 2018;52:127-38.
30 Jiang J, Yuan Z, Sun Y, Bu Y, Li W, Fei Z, et al. Ginsenoside Rg3 enhances the anti-proliferative activity of erlotinib in pancreatic cancer cell lines by downregulation of EGFR/PI3K/Akt signaling pathway. Biomed Pharmacother 2017;96:619-25.   DOI
31 Sivonova MK, Vilckova M, Kliment J, Mahmood S, Jurecekova J, Dusenkova S, et al. Association of p53 and p21 polymorphisms with prostate cancer. Biomed Rep 2015;3:707-14.   DOI
32 Hemann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ 2006;13:1256-9.   DOI
33 Quinn LM, Richardson H. Bcl-2 in cell cycle regulation. Cell Cycle 2014;3:6-8.   DOI
34 Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, et al. Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 2005;25:7432-40.   DOI
35 Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, et al. Expression of DRD2 is increased in human pancreatic ductal adenocarcinoma and inhibitors slow tumor growth in mice. Gastroenterology 2016;151:1218-31.   DOI
36 Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc 2009;84:632-7. quiz 638.   DOI
37 Karikas GA. Anticancer and chemopreventing natural products: some biochemical and therapeutic aspects. J BUON 2010;15:627-38.
38 Burdak-Rothkamm S, Rothkamm K, McClelland K, Al Rashid ST, Prise KM. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells. Cancer Lett 2015;356:454-61.   DOI
39 Fagerholm R, Sprott K, Heikkinen T, Bartkova J, Heikkila P, Aittomaki K, et al. Overabundant FANCD2, alone and combined with NQO1, is a sensitive marker of adverse prognosis in breast cancer. Ann Oncol 2013;24:2780-5.   DOI
40 Pin E, Henjes F, Hong MG, Wiklund F, Magnusson P, Bjartell A. Identification of a novel autoimmune peptide epitope of prostein in prostate cancer. J Proteome Res 2017;16:204-16.   DOI
41 Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014;65:1046-55.   DOI
42 Chaturvedi S, Garcia JA. Novel agents in the management of castration resistant prostate cancer. J Carcinog 2014;13:5.   DOI
43 Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-38.   DOI
44 Klabunde T, Hessler G. Drug design strategies for targeting G-proteincoupled receptors. Chembiochem 2002;3:928-44.   DOI
45 Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61.   DOI
46 Kim Hogyoung, Datta A, Talwar Sudha, Saleem Sarmad N, Mondal Debasis, Abdel-Mageed Asim B. Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion. Oncotarget 2017;8.
47 Shen C, Oswald D, Phelps D, Cam H, Pelloski CE, Pang Q, et al. Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. Cancer Res 2013;73:3393-401.   DOI
48 Shan X, Fu YS, Aziz F, Wang XQ, Yan Q, Liu JW, et al. Ginsenoside Rg3 inhibits melanoma cell proliferation through down-regulation of histone deacetylase 3 (HDAC3) and increase of p53 acetylation. PLoS One 2014;9:e115401.   DOI
49 Levy DE, Lee CK. What does Stat3 do? J Clin Invest 2002;109:1143-8.   DOI
50 Cai G, Laslett LL, Aitken D, Halliday A, Pan F, Otahal P, et al. Effect of zoledronic acid and denosumab in patients with low back pain and modic change: a proof-of-principle trial. J Bone Miner Res 2018;33:773-82.   DOI
51 Liang QL, Liang XP, Wang YM, Xie YY, Zhang RL, Chen X, et al. Effective components screening and anti-myocardial infarction mechanism study of the Chinese medicine NSLF6 based on "system to system" mode. J Transl Med 2012;10:26.   DOI
52 Ng DP, Poulsen BE, Deber CM. Membrane protein misassembly in disease. Biochim Biophys Acta 2012;1818:1115-22.   DOI
53 Kim HS, Lee H, Shin SJ, Beom SH, Jung M, Bae S, Lee EY, Park KH, Choi YY, Son T, et al. Complementary utility of targeted next-generation sequencing and immunohistochemistry panels as a screening platform to select targeted therapy for advanced gastric cancer. Oncotarget 2017;8(24):38389-98.   DOI
54 Zhang HY, Cui J, Zhang Y, Wang ZL, Chong T, Wang ZM, et al. Isoflavones and prostate cancer: a review of some critical issues. Chin Med J (Engl) 2016;129:341-7.   DOI
55 Guo Y, Zhi F, Chen P, Zhao K, Xiang H, Mao Q, et al. Green tea and the risk of prostate cancer: a systematic review and meta-analysis. Medicine (Baltimore) 2017;96:e6426.   DOI
56 Lang A, Neuhaus J, Pfeiffenberger M, Schroder E, Ponomarev I, Weber Y, et al. Optimization of a nonviral transfection system to evaluate Cox-2 controlled interleukin-4 expression for osteoarthritis gene therapy in vitro. J Gene Med 2014;16:352-63.   DOI
57 Bostwick DG, Burke HB, Djakiew D, Euling S, Ho SM, Landolph J, et al. Human prostate cancer risk factors. Cancer 2004;101:2371-490.   DOI
58 Pounis G, Tabolacci C, Costanzo S, Cordella M, Bonaccio M, Rago L, et al. Reduction by coffee consumption of prostate cancer risk: evidence from the Moli-sani cohort and cellular models. Int J Cancer 2017;141:72-82.   DOI
59 Nilsson S, Strang P, Aksnes AK, Franzen L, Olivier P, Pecking A, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer 2012;48:678-86.   DOI
60 Gordaliza M. Natural products as leads to anticancer drugs. Clin Transl Oncol 2007;9:767-76.   DOI
61 Zhou SS, Xu JD, Zhu H, Shen H, Xu J, Mao Q, et al. Simultaneous determination of original, degraded ginsenosides and aglycones by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry for quantitative evaluation of Du-Shen-Tang, the decoction of ginseng. Molecules 2014;19:4083-104.   DOI
62 Yang X, Zou J, Cai H, Huang X, Yang X, Guo D, et al. Ginsenoside Rg3 inhibits colorectal tumor growth via down-regulation of C/EBPbeta/NF-kappaB signaling. Biomed Pharmacother 2017;96:1240-5.   DOI
63 Huang G, Khan I, Li X, Chen L, Leong W, Ho LT, et al. Ginsenosides Rb3 and Rd reduce polyps formation while reinstate the dysbiotic gut microbiota and the intestinal microenvironment in Apc(Min/+) mice. Sci Rep 2017;7:12552.   DOI
64 Gioti K, Tenta R. Bioactive natural products against prostate cancer: mechanism of action and autophagic/apoptotic molecular pathways. Planta Med 2015;81:543-62.   DOI
65 Kou N, Xue M, Yang L, Zang MX, Qu H, Wang MM, et al. Panax quinquefolius saponins combined with dual antiplatelet drug therapy alleviate gastric mucosal injury and thrombogenesis through the COX/PG pathway in a rat model of acute myocardial infarction. PLoS One 2018;13:e0194082.   DOI
66 Shishtar E, Sievenpiper JL, Djedovic V, Cozma AI, Ha V, Jayalath VH, et al. The effect of ginseng (the genus panax) on glycemic control: a systematic review and meta-analysis of randomized controlled clinical trials. PLoS One 2014;9:e107391.   DOI
67 Kim HS, Lee EH, Ko SR, Choi KJ, Park JH, Im DS, et al. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch Pharm Res 2004;27:429-35.   DOI
68 Bae JS, Park HS, Park JW, Li SH, Chun YS. Red ginseng and 20(S)-Rg3 control testosterone-induced prostate hyperplasia by deregulating androgen receptor signaling. J Nat Med 2012;66:476-85.   DOI
69 Han SY, Li HX, Ma X, Zhang K, Ma ZZ, Jiang Y, et al. Evaluation of the anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and Carthamus tinctorius in rats. J Ethnopharmacol 2013;145:722-7.   DOI
70 Kim JK, Kim JY, Kim HJ, Park KG, Harris RA, Cho WJ, et al. Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity. PLoS One 2013;8:e80391.   DOI
71 Bretz AC, Gittler MP, Charles JP, Gremke N, Eckhardt I, Mernberger M, et al. DeltaNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma. Nucleic Acids Res 2016;44:3204-18.   DOI
72 Pellecchia A, Pescucci C, De Lorenzo E, Luceri C, Passaro N, Sica M, et al. Overexpression of ETV4 is oncogenic in prostate cells through promotion of both cell proliferation and epithelial to mesenchymal transition. Oncogenesis 2012;1:e20.   DOI
73 Liu D, Liu T, Teng Y, Chen W, Zhao L, Li X, et al. Ginsenoside Rb1 inhibits hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells by regulating microRNA-25. Exp Ther Med 2017;14:2895-902.   DOI
74 Deng S, Wong CKC, Lai HC, Wong AST. Ginsenoside-Rb1 targets chemotherapy-resistant ovarian cancer stem cells via simultaneous inhibition of Wnt/beta-catenin signaling and epithelial-to-mesenchymal transition. Oncotarget 2017;8:25897-914.   DOI
75 Willis S, Day CL, Hinds MG, Huang DC. The Bcl-2-regulated apoptotic pathway. J Cell Sci 2003;116:4053-6.   DOI
76 Kim YS, Woo JY, Han CK, Chang IM. Safety analysis of panax ginseng in randomized clinical trials: a systematic review. Medicines (Basel) 2015;2:106-26.   DOI
77 Li W, Yan MH, Liu Y, Liu Z, Wang Z, Chen C, et al. Ginsenoside Rg5 ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of inflammation, oxidative stress, and apoptosis. Nutrients 2016;8.
78 Schlag EM, McIntosh MS. Ginsenoside content and variation among and within American ginseng (Panax quinquefolius L.) populations. Phytochemistry 2006;67:1510-9.   DOI
79 Paek AL, Liu JC, Loewer A, Forrester WC, Lahav G. Cell-to-Cell variation in p53 dynamics leads to fractional killing. Cell 2016;165:631-42.   DOI
80 Catz SD, Johnson J. BCL-2 in prostate cancer: a minireview. Apoptosis 2003;8:29-37.   DOI
81 Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, et al. TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One 2011;6:e21650.   DOI
82 Peverelli E, Giardino E, Treppiedi D, Locatelli M, Vaira V, Ferrero S, et al. Dopamine receptor type 2 (DRD2) inhibits migration and invasion of human tumorous pituitary cells through ROCK-mediated cofilin inactivation. Cancer Lett 2016;381:279-86.   DOI
83 Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp 2014.
84 Pan XY, Guo H, Han J, Hao F, An Y, Xu Y, et al. Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells. Eur J Pharmacol 2012;683:27-34.   DOI
85 Liu J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R, et al. Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia 2010;81:902-5.   DOI
86 Fan TP, Deal G, Koo HL, Rees D, Sun H, Chen S, et al. Future development of global regulations of Chinese herbal products. J Ethnopharmacol 2012;140:568-86.   DOI
87 Piccolella M, Crippa V, Messi E, Tetel MJ, Poletti A. Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells. Pharmacol Res 2014;79:13-20.   DOI
88 Kang Jia, Chong SJF, Ooi Vignette Zi Qi, Vali Shireen, Kumar Ansu, Kapoor Shweta, Abbasi Taher, Hirpara Jayshree L, Loh Thomas, Goh Boon Cher, et al. Overexpression of Bcl-2 induces STAT-3 activation via an increase in mitochondrial superoxide. Oncotarget 2015;6(33).
89 Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood 2002;100:2414-20.   DOI
90 Barton DL, Soori GS, Bauer BA, Sloan JA, Johnson PA, Figueras C, et al. Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. Support Care Cancer 2010;18:179-87.   DOI
91 Jiang Z, Yang Y, Yang Y, Zhang Y, Yue Z, Pan Z, et al. Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune. Biomed Pharmacother 2017;96:378-83.   DOI
92 Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-91.   DOI
93 XueM, Yang L, Shi DZ, Radauer C, Breiteneder H,Ma Y, et al. Qualitative analysis of xinyue capsules by high-performance liquid chromatography: preliminary evaluation of drug quality in a Sino-Austrian joint study. Chin J Integr Med 2015;21:772-7.   DOI
94 Kim SK, Chung JH, Lee BC, Lee SW, Lee KH, Kim YO, et al. Influence of panax ginseng on alpha-adrenergic receptor of benign prostatic hyperplasia. Int Neurourol J 2014;18:179-86.   DOI
95 Pietsch EC, Humbey O, Murphy ME. Polymorphisms in the p53 pathway. Oncogene 2006;25:1602-11.   DOI
96 Wang H, He Z, Zhang C, Zhang L, Xu D. Transmembrane protein alignment and fold recognition based on predicted topology. PLoS One 2013;8:e69744.   DOI
97 Hong MG, Karlsson R, Magnusson PK, Lewis MR, et al. A genome-wide assessment of variability in human serum metabolism. Hum Mutat 2013;34:515-24.   DOI
98 Nguyen JK, Magi-Galluzzi C. Unfavorable pathology, tissue biomarkers and genomic tests with clinical implications in prostate cancer management. Adv Anat Pathol 2018;25:293-303.   DOI
99 Sadeghi-Gandomani HR, Yousefi M, Rahimi S, Yousefi S, Karimi-Rozveh A, Hosseini S, Mahabadi AA, Abarqui HF, Borujeni NN, Salehiniya H. The incidence, risk factors, and knowledge about the prostate cancer through worldwide and Iran. WCRJ 2017;4(4):e972. 2017.
100 Bilani N, Bahmad H, Abou-Kheir W. Prostate cancer and aspirin use: synopsis of the proposed molecular mechanisms. Front Pharmacol 2017;8:145.
101 Tyner AL, Gartel AL. The role of the cyclin-dependent kinase inhibitor p21. Molecular Cancer Therapeutics 2002;1:639-49.
102 Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C, et al. WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J Biol Chem 2006;281:8600-6.   DOI
103 Gaudreau PO, Stagg J, Soulieres D, Saad F. The present and future of bio-markers in prostate cancer: proteomics, genomics, and immunology advancements. Biomark Cancer 2016;8:15-33.
104 Soares ND, Machado CL, Trindade BB, Lima IC, Gimba ER, Teodoro AJ, et al. Lycopene extracts from different tomato-based food products induce apoptosis in cultured human primary prostate cancer cells and regulate TP53, Bax and Bcl-2 transcript expression. Asian Pac J Cancer Prev 2017;18:339-45.
105 Lewiecki EM. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis. Drug Healthc Patient Saf 2011;3:79-91.   DOI
106 Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O. Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev 2017;10. CD012432.
107 Attele Anoja S, Wu JA, Yuan C-S. Ginseng pharmacology Multiple constituents and multiple actions. Biochemical Pharmacology 1999;58:1685-93.   DOI
108 Chang YD, Smith J, Portman D, Kim R, Oberoi-Jassal R, Rajasekhara S, et al. Single institute experience with methylphenidate and American Ginseng in cancer-related fatigue. Am J Hosp Palliat Care 2018;35:144-50.   DOI
109 Barton DL, Liu H, Dakhil SR, Linquist B, Sloan JA, Nichols CR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst 2013;105:1230-8.   DOI