Anti-cancer effects of aloe-emodin: a systematic review
Background: Anthraquinones are a possible treatment option for oncological patients due to their anti-cancer properties. Cancer patients often exhaust a plethora of resources that ultimately fail to provide fully curative measures. Alternative treatments are subsequently sought in the hope of finding a therapeutic remedy. Potential regimens include aloe-emodin and its related derivatives. This review therefore summarizes the effects of aloe-emodin and other aloe components in light of their anti-proliferative and anti-carcinogenic properties.
Methods: A systematic search was performed in PubMed for aloe-emodin and cancer in humans. Sixty ab-stracts of in vitro studies were selected and reviewed with subsequent screening of the full text. Thirty-eight articles were summarized. Results: Aloe-emodin possesses multiple anti-proliferative and anti-carcinogenic properties in a host of human cancer cell lines, with often multiple vital pathways affected by the same molecule. The most notable effects include inhibition of cell proliferation, migration, and invasion; cycle arrest; induction of cell death; mitochondrial membrane and redox perturbations; and modulation of immune signaling. The effects of al-oe-emodin are not ubiquitous across all cell lines but depend on cell type.
Conclusions: On the basis of this systematic review, the multiple consistent effects of aloe-emodin in hu-man-derived cancer cell lines suggest that aloe-emodin is a potential anti-cancer agent that acts on cancer cells in a pleiotropic manner.
Relevance for patients: Cancer patients often utilize alternative therapies as a result of suboptimal efficacy of conventional treatments. Aloe-emodin might become a therapeutic option for cancer patients if the basic research is confirmed in clinical trials.
[1] US Cancer Statistics Working Group. United states cancer statistics: 1999-2012 incidence and mortality web-based report. Atlanta, 2015.
[2] Henley SJ, Singh SD, King J, Wilson R, O'Neil ME, Ryerson AB. Invasive cancer incidence and survival--united states, 2011. MMWR Morb Mortal Wkly Rep 2015; 64: 237-242.
[3] Vogel A. Anthraquinone. Ullmann's encyclopedia of industrial chemistry. Weinheim, Germany, Wiley-VCH, 2000.
[4] Barcroft A, Myskja A. Aloe vera: Nature's silent healer. United Kingdom, BAAM, 2003.
[5] Choi S, Chung M-H. A review on the relationship between aloe vera components and their biologic effects. Seminars in Integrative Medicine 2003; 1: 53-62.
[6] Ni Y, Turner D, Yates KM, Tizard I. Isolation and characterization of structural components of aloe vera l. Leaf pulp. Int Immunopharmacol 2004; 4: 1745-1755.
[7] Lin JG, Chen GW, Li TM, Chouh ST, Tan TW, Chung JG. Aloe-emodin induces apoptosis in t24 human bladder cancer cells through the p53 dependent apoptotic pathway. J Urol 2006; 175: 343-347.
[8] Guo JM, Xiao BX, Liu Q, Zhang S, Liu DH, Gong ZH. Anticancer effect of aloe-emodin on cervical cancer cells involves g2/m arrest and induction of differentiation. Acta Pharmacol Sin 2007; 28: 1991-1995.
[9] Schorkhuber M, Richter M, Dutter A, Sontag G, Marian B. Effect of anthraquinone-laxatives on the proliferation and urokinase secretion of normal, premalignant and malignant colonic epithelial cells. Eur J Cancer 1998; 34: 1091-1098.
[10] Suboj P, Babykutty S, Valiyaparambil Gopi DR, Nair RS, Srinivas P, Gopala S. Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating mmp-2/9, rhob and vegf via reduced DNA binding activity of nf-kappab. Eur J Pharm Sci 2012; 45: 581-591.
[11] Suboj P, Babykutty S, Srinivas P, Gopala S. Aloe emodin induces g2/m cell cycle arrest and apoptosis via activation of caspase-6 in human colon cancer cells. Pharmacology 2012; 89: 91-98.
[12] Chen SH, Lin KY, Chang CC, Fang CL, Lin CP. Aloe-emodininduced apoptosis in human gastric carcinoma cells. Food Chem Toxicol 2007; 45: 2296-2303.
[13] Chihara T, Shimpo K, Beppu H, Yamamoto N, Kaneko T, Wakamatsu K, Sonoda S. Effects of aloe-emodin and emodin on proliferation of the mkn45 human gastric cancer cell line. Asian Pac J Cancer Prev 2015; 16: 3887-3891.
[14] Guo J, Xiao B, Liu Q, Gong Z, Le Y. Suppression of c-myc expression associates with anti-proliferation of aloe-emodin on gastric cancer cells. Cancer Invest 2008; 26: 369-374.
[15] Tabolacci C, Oliverio S, Lentini A, Rossi S, Galbiati A, Montesano C, Mattioli P, Provenzano B, Facchiano F, Beninati S. Aloe-emodin as antiproliferative and differentiating agent on human u937 monoblastic leukemia cells. Life Sci 2011; 89: 812-820.
[16] Lai MY, Hour MJ, Wing-Cheung LH, Yang WH, Lee HZ. Chaperones are the target in aloe-emodin-induced human lung nonsmall carcinoma h460 cell apoptosis. Eur J Pharmacol 2007; 573: 1-10.
[17] Lee HZ. Protein kinase c involvement in aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell. Br J Pharmacol 2001; 134: 1093-1103.
[18] Lee HZ, Hsu SL, Liu MC, Wu CH. Effects and mechanisms of aloe-emodin on cell death in human lung squamous cell carcinoma. Eur J Pharmacol 2001; 431: 287-295.
[19] Lee HZ, Wu CH, Chang SP. Release of nucleophosmin from the nucleus: Involvement in aloe-emodin-induced human lung non small carcinoma cell apoptosis. Int J Cancer 2005; 113: 971-976.
[20] Lee HZ, Lin CJ, Yang WH, Leung WC, Chang SP. Aloe-emodin induced DNA damage through generation of reactive oxygen species in human lung carcinoma cells. Cancer Lett 2006; 239: 55-63.
[21] Lee HZ, Yang WH, Hour MJ, Wu CY, Peng WH, Bao BY, Han PH, Bau DT. Photodynamic activity of aloe-emodin induces resensitization of lung cancer cells to anoikis. Eur J Pharmacol 2010; 648: 50-58.
[22] Yeh FT, Wu CH, Lee HZ. Signaling pathway for aloe-emodin-induced apoptosis in human h460 lung nonsmall carcinoma cell. Int J Cancer 2003; 106: 26-33.
[23] Jeon W, Jeon YK, Nam MJ. Apoptosis by aloe-emodin is mediated through down-regulation of calpain-2 and ubiquitin-protein ligase e3a in human hepatoma huh-7 cells. Cell Biol Int 2012; 36: 163-167.
[24] Lu GD, Shen HM, Chung MC, Ong CN. Critical role of oxidative stress and sustained jnk activation in aloe-emodin-mediated apoptotic cell death in human hepatoma cells. Carcinogenesis 2007; 28: 1937-1945.
[25] Lin ML, Lu YC, Chung JG, Li YC, Wang SG, SH NG, Wu CY, Su HL, Chen SS. Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Lett 2010; 291: 46-58.
[26] Lin ML, Lu YC, Chung JG, Wang SG, Lin HT, Kang SE, Tang CH, Ko JL, Chen SS. Down-regulation of mmp-2 through the p38 mapk-nf-kappab-dependent pathway by aloe-emodin leads to inhibition of nasopharyngeal carcinoma cell invasion. Mol Carcinog 2010; 49: 783-797.
[27] Pecere T, Sarinella F, Salata C, Gatto B, Bet A, Dalla VF, Diaspro A, Carli M, Palumbo M, Palu G. Involvement of p53 in specific anti-neuroectodermal tumor activity of aloe-emodin. Int J Cancer 2003; 106: 836-847.
[28] Acevedo-Duncan M, Russell C, Patel S, Patel R. Aloe-emodin modulates pkc isozymes, inhibits proliferation, and induces apoptosis in u-373mg glioma cells. Int Immunopharmacol 2004; 4: 1775-1784.
[29] Ismail S, Haris K, bdul Ghani AR, Abdullah JM, Johan MF, Mohamed Yusoff AA. Enhanced induction of cell cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human u87 malignant glioma cells by aloe emodin. J Asian Nat Prod Res 2013; 15: 1003-1012.
[30] Xiao B, Guo J, Liu D, Zhang S. Aloe-emodin induces in vitro g2/m arrest and alkaline phosphatase activation in human oral cancer kb cells. Oral Oncol 2007; 43: 905-910.
[31] He TP, Yan WH, Mo LE, Liang NC. Inhibitory effect of aloe-emodin on metastasis potential in ho-8910pm cell line. J Asian Nat Prod Res 2008; 10: 383-390.
[32] Liu K, Park C, Li S, Lee KW, Liu H, He L, Soung NK, Ahn JS, Bode AM, Dong Z, Kim BY, Dong Z. Aloe-emodin suppresses prostate cancer by targeting the mtor complex 2. Carcinogenesis 2012; 33: 1406-1411.
[33] Chou TH, Liang CH. The molecular effects of aloe-emodin (ae)/liposome-ae on human nonmelanoma skin cancer cells and skin permeation. Chem Res Toxicol 2009; 22: 2017-2028.
[34] Lin SY, Yang JH, Hsia TC, Lee JH, Chiu TH, Wei YH, Chung JG. Effect of inhibition of aloe-emodin on n-acetyltransferase activity and gene expression in human malignant melanoma cells (a375.S2). Melanoma Res 2005; 15: 489-494.
[35] Fenig E, Nordenberg J, Beery E, Sulkes J, Wasserman L. Combined effect of aloe-emodin and chemotherapeutic agents on the proliferation of an adherent variant cell line of merkel cell carcinoma. Oncol Rep 2004; 11: 213-217.
[36] Radovic J, Maksimovic-Ivanic D, Timotijevic G, Popadic S, Ramic Z, Trajkovic V, Miljkovic D, Stosic-Grujicic S, Mijatovic S. Cell-type dependent response of melanoma cells to aloe emodin. Food Chem Toxicol 2012; 50: 3181-3189.
[37] Wasserman L, Avigad S, Beery E, Nordenberg J, Fenig E. The effect of aloe emodin on the proliferation of a new merkel carcinoma cell line. Am J Dermatopathol 2002; 24: 17-22.
[38] Chen YY, Chiang SY, Lin JG, Yang JS, Ma YS, Liao CL, Lai TY, Tang NY, Chung JG. Emodin, aloe-emodin and rhein induced DNA damage and inhibited DNA repair gene expression in scc-4 human tongue cancer cells. Anticancer Res 2010; 30: 945-951.
[39] Chen YY, Chiang SY, Lin JG, Ma YS, Liao CL, Weng SW, Lai TY, Chung JG. Emodin, aloe-emodin and rhein inhibit migration and invasion in human tongue cancer scc-4 cells through the inhibition of gene expression of matrix metalloproteinase-9. Int J Oncol 2010; 36: 1113-1120.
[40] Chiu TH, Lai WW, Hsia TC, Yang JS, Lai TY, Wu PP, Ma CY, Yeh CC, Ho CC, Lu HF, Wood WG, Chung JG. Aloe-emodin induces cell death through s-phase arrest and caspase-dependent pathways in human tongue squamous cancer scc-4 cells. Anticancer Res 2009; 29: 4503-4511.
[41] Lin ML, Lu YC, Su HL, Lin HT, Lee CC, Kang SE, Lai TC, Chung JG, Chen SS. Destabilization of carp mrnas by aloeemodin contributes to caspase-8-mediated p53-independent apoptosis of human carcinoma cells. J Cell Biochem 2011; 112: 1176-1191.
[42] Lissoni P, Rovelli F, Brivio F, Zago R, Colciago M, Messina G, Mora A, Porro G. A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus aloe arborescens in patients with metastatic cancer. In Vivo 2009; 23: 171-175.
