Multi-Targeting by β-Elemene and Its Anticancer Properties: A Good Choice for Oncotherapy and Radiochemotherapy Sensitization

References

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394–424, 2018. doi: 10.3322/caac.21492
   PubMed Web of Science ®Google Scholar
• Park W, Amin AR, Chen ZG, and Shin DM: New perspectives of curcumin in cancer prevention. Cancer Prev Res (Phila) 6, 387–400, 2013. doi: 10.1158/1940-6207.capr-12-0410
   PubMed Web of Science ®Google Scholar
• Kunnumakkara AB, Anand P, and Aggarwal BB: Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269, 199–225, 2008. doi: 10.1016/j.canlet.2008.03.009
   PubMed Web of Science ®Google Scholar
• Sporn MB, Dunlop NM, Newton DL, and Smith JM: Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 35, 1332–1338, 1976.
   PubMedGoogle Scholar
• Shankar E, Kanwal R, Candamo M, and Gupta S: Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol 40–41, 82–99, 2016. doi: 10.1016/j.semcancer.2016.04.002
   PubMed Web of Science ®Google Scholar
• Guo YT: Isolation and identification of elemene from the essential oil of Curcuma wenyujin. Zhong Yao Tong Bao 8, 31, 1983.
   PubMedGoogle Scholar
• Tang XH, Qin SK, and Xie T: Status and progress of basic researches of elemene injection for anti-tumor. Chin Clin Oncol 15, 266–273, 2010.
   Google Scholar
• Yao YQ, Ding X, Jia YC, Huang CX, Wang YZ, et al. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett 264, 127–134, 2008. doi: 10.1016/j.canlet.2008.01.049
   PubMed Web of Science ®Google Scholar
• Xu HB, Zheng LP, Li L, Xu LZ, and Fu J: Elemene, one ingredient of a Chinese herb, against malignant tumors: a literature-based meta-analysis. Cancer Invest 31, 156–166, 2013. doi: 10.3109/07357907.2012.756108
   PubMed Web of Science ®Google Scholar
• Zhang R, Tian A, Zhang H, Zhou Z, Yu H, et al. Amelioration of experimental autoimmune encephalomyelitis by beta-elemene treatment is associated with Th17 and Treg cell balance. J Mol Neurosci 44, 31–40, 2011. doi: 10.1007/s12031-010-9483-1
   PubMed Web of Science ®Google Scholar
• Wang G, Li X, Huang F, Zhao J, Ding H, et al. Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci 62, 881–893, 2005. doi: 10.1007/s00018-005-5017-3
   PubMed Web of Science ®Google Scholar
• Sun Y, Liu G, Zhang Y, Zhu H, Ren Y, et al. Synthesis and in vitro anti-proliferative activity of beta-elemene monosubstituted derivatives in HeLa cells mediated through arrest of cell cycle at the G1 phase. Bioorg Med Chem 17, 1118–1124, 2009. doi: 10.1016/j.bmc.2008.12.040
   PubMed Web of Science ®Google Scholar
• Wang Y, Deng Y, Mao S, Jin S, Wang J, et al. Characterization and body distribution of beta-elemene solid lipid nanoparticles (SLN). Drug Dev Ind Pharm 31, 769–778, 2005. doi: 10.1080/03639040500216329
   PubMed Web of Science ®Google Scholar
• Wang JW, Zhang HP, and Sun Y: Results of phase II clinical trials of elemene emulsion in the management of advanced malignancies. J New Drug China 4, 26–30, 1995.
   Google Scholar
• Sheng LI, You-Wei XU, Ren DW, Zheng JH, and Xiao-Jun MA: Preparation of β-elemene calcium alginate-chitosan microcapsules. Chin J Pharm 35, 17–20, 2004.
   Google Scholar
• Zhang XY, Deng YJ, Wang XM, Hao YL, and Yy W: Study on pharmacokinetics of PVP coated β-elemene liposome in rats. J New Drug China 15, 157–160, 2006.
   Google Scholar
• Zhang XY: Optimal preparation of PVP-complexedβ-elemene liposomes. Chin J New Drugs 15, 204–207, 2006.
   Google Scholar
• Wang Y, Jin S, Deng Y, Zheng J, and Bi D: Determination of β-elemene in solid lipid nanoparticles by RP-HPLC. J Shenyang Pharm Univ 22, 286–288, 2005.
   Google Scholar
• Li Z, Wang K, Chen YR, Wu XY, and Su CY: [Studies on metabolite of beta-elemene in rat bile]. Yao Xue Xue Bao 35, 829–831, 2000.
   PubMedGoogle Scholar
• Chen JC, Duan WL, Bai RR, Yao HQ, Wu XM, et al. Synthesis of 13-beta-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells. Chin J Nat Med 13, 618–627, 2015. doi: 10.1016/s1875-5364(15)30058-3
   PubMed Web of Science ®Google Scholar
• Xu L, Tao S, Wang X, Yu Z, Wang M, et al. The synthesis and anti-proliferative effects of beta-elemene derivatives with mTOR inhibition activity. Bioorg Med Chem 14, 5351–5356, 2006. doi: 10.1016/j.bmc.2006.03.041
   PubMed Web of Science ®Google Scholar
• Chen J, Duan W, Bai R, Yao H, Shang J, et al. Design, synthesis and antioxidant activity evaluation of novel beta-elemene derivatives. Bioorg Med Chem Lett 24, 3407–3411, 2014. doi: 10.1016/j.bmcl.2014.05.078
   PubMed Web of Science ®Google Scholar
• Wang K, Li Z, Chen Y, and Su C: The pharmacokinetics of a novel anti-tumor agent, beta-elemene, in Sprague-Dawley rats. Biopharm Drug Dispos 26, 301–307, 2005. doi: 10.1002/bdd.463
   PubMed Web of Science ®Google Scholar
• Shi F, Yang G, Ren J, Guo T, Du Y, et al. Formulation design, preparation, and in vitro and in vivo characterizations of β-elemene-loaded nanostructured lipid carriers. Int J Nanomed 8, 2533–2541, 2013. doi: 10.2147/ijn.s46578
   PubMed Web of Science ®Google Scholar
• Zeng Z, Zhou G, Wang X, Huang EZ, Zhan X, et al. Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion. Int J Nanomed 5, 567–572, 2010.
   PubMed Web of Science ®Google Scholar
• Song XD, Liu HM, Hua W, Di D, and Lin-Hua WU: Tissue distribution of β-elemene liposomes in rats. Chin Pharm J 42, 1480–1482, 2007.
   Google Scholar
• Wu LH, Song XD, Liu HM, Wei H DD, et al. Pharmacokinetic study of β-elemene liposome in rats. Chin J Traditional Med Sci Technol 42, 425–426, 2007.
   Google Scholar
• Gu B, Hu J, Liu H, Sun X, and Zhu Y: Effect of the combination of elemene and concurrent chemoradiation with cisplatin followed by consolidation chemotherapy with cisplatin and fluorouracil for locally advanced esophageal cancer. Chin J Clin Oncol 40, 600–603, 2013. doi: 10.3969/j.issn.1000-8179.2013.10.012
   Google Scholar
• Yin ZM, Zhang Y, and Xie Z: Elemene plus fluorouracil in the treatment of advanced gastric cancer. Chin J Clin Oncol 23, 810–812, 1996.
   Google Scholar
• Dong H, Jin F, Wu WL, Chen H, Huang W, et al. Postoperative radiotherapy combined with elemene for brain glioma. Chin J Clin Oncol 35, 858–860, 2008.
   Google Scholar
• Wang J, and Zhang H,YS: Phase III clinical trial of elemenum emulsion in the management of malignant pleural and peritoneal effusions. Zhonghua Zhong Liu Za Zhi 18, 464–467, 1996.
   PubMedGoogle Scholar
• Jianjun Q, Song Z, Yin L, Jia Z, and Donglei L: Treatment of chylothorax with elemene. Thorac Cardiovasc Surg 56, 103–105, 2008. doi: 10.1055/s-2007-965708
   PubMed Web of Science ®Google Scholar
• Hunger SP, and Mullighan CG: Acute lymphoblastic leukemia in children. N Engl J Med 373, 1541–1552, 2015. doi: 10.1056/NEJMra1400972
   PubMed Web of Science ®Google Scholar
• Zou L, Liu W, and Yu L: beta-elemene induces apoptosis of K562 leukemia cells . Zhonghua Zhong Liu Za Zhi 23, 196–198, 2001.
   PubMedGoogle Scholar
• Zheng C, Cai X, Wu S, Liu Z, Shi Y, et al. Enhancing effect of beta-elemene emulsion on chemotherapy with harringtonine, aclacinomycin, and Ara-c in treatment of refractory/relapsed acute myeloid leukemia. Pak J Med Sci 30, 1270–1272, 2014. doi: 10.12669/pjms.306.5207
   PubMed Web of Science ®Google Scholar
• Wang Y, and Fang MY: Effect of ginseng saponin, arsenic trioxide, beta-elemene combined with CTX on telomere-telomerase system in K562 cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi 14, 1089–1095, 2006.
   PubMedGoogle Scholar
• Zhang Y, Mu XD, Li EZ, Luo Y, Song N, et al. The role of E3 ubiquitin ligase Cbl proteins in beta-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells. Int J Mech Sci 14, 10075–10089, 2013. doi: 10.3390/ijms140510075
   Web of Science ®Google Scholar
• Enzinger PC, and Mayer RJ: Esophageal cancer. N Engl J Med 349, 2241–2252, 2003. doi: 10.1056/NEJMra035010
   PubMed Web of Science ®Google Scholar
• Thallinger CM, Raderer M, and Hejna M: Esophageal cancer: a critical evaluation of systemic second-line therapy. J Clin Oncol 29, 4709–4714, 2011. doi: 10.1200/jco.2011.36.7599
   PubMed Web of Science ®Google Scholar
• Wang CM, Wu QQ, Li SQ, Chen FJ, Tuo L, et al. Upregulation of the long non-coding RNA PlncRNA-1 promotes esophageal squamous carcinoma cell proliferation and correlates with advanced clinical stage. Dig Dis Sci 59, 591–597, 2014. doi: 10.1007/s10620-013-2956-7
   PubMed Web of Science ®Google Scholar
• Li J, Chen Z, Tian L, Zhou C, He MY, et al. LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma. Gut 63, 1700–1710, 2014. doi: 10.1136/gutjnl-2013-305806
   PubMed Web of Science ®Google Scholar
• Xie HW, Wu QQ, Zhu B, Chen FJ, Ji L, et al. Long noncoding RNA SPRY4-IT1 is upregulated in esophageal squamous cell carcinoma and associated with poor prognosis. Tumor Biol 35, 7743–7754, 2014. doi: 10.1007/s13277-014-2013-y
   PubMedGoogle Scholar
• Hu Z, Wu H, Li Y, Hou Q, Wang Y, et al. beta-elemene inhibits the proliferation of esophageal squamous cell carcinoma by regulating long noncoding RNA-mediated inhibition of hTERT expression. Anticancer Drugs 26, 531–539, 2015. doi: 10.1097/cad.0000000000000216
   PubMed Web of Science ®Google Scholar
• Chang Z, Gao M, Zhang W, Song L, Jia Y, et al. Beta-elemene treatment is associated with improved outcomes of patients with esophageal squamous cell carcinoma. Surg Oncol 26, 333–337, 2017. doi: 10.1016/j.suronc.2017.07.002
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Sagaert X, Topal B, Haustermans K, and Prenen H: Gastric cancer. Lancet 388, 2654–2664, 2016. doi: 10.1016/s0140-6736(16)30354-3
   PubMed Web of Science ®Google Scholar
• Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49, 1374–1403, 2013. doi: 10.1016/j.ejca.2012.12.027
   PubMed Web of Science ®Google Scholar
• Liu J, Liu X, Qiu G, Zhang Z, Fan L, et al. Effects of β-elemene on proliferation and apoptosis of SGC7901 gastric cancer cells in vitro and the underlying mechanisms . Nan Fang Yi Ke Da Xue Xue Bao 35, 1234–1238, 2015.
   PubMedGoogle Scholar
• Liu JS, Che XM, Chang S, Qiu GL, He SC, et al. beta-elemene enhances the radiosensitivity of gastric cancer cells by inhibiting Pak1 activation. World J Gastroenterol 21, 9945–9956, 2015. doi: 10.3748/wjg.v21.i34.9945
   PubMed Web of Science ®Google Scholar
• Liu J, Zhang Y, Qu J, Xu L, Hou K, et al. beta-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis. BMC Cancer 11, 183, 2011. doi: 10.1186/1471-2407-11-183
   PubMed Web of Science ®Google Scholar
• Chen X, Wang Y, Luo H, Luo Z, Zhang T, et al. β-elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1. Mol Med Rep 6, 989–995, 2012. doi: 10.3892/mmr.2012.1018
   PubMed Web of Science ®Google Scholar
• Li QQ, Wang G, Liang H, Li JM, Huang F, et al. β-Elemene promotes cisplatin-induced cell death in human bladder cancer and other carcinomas. Anticancer Res 33, 1421–1428, 2013.
   PubMed Web of Science ®Google Scholar
• Lu X, Wang Y, Luo H, Qiu W, Han H, et al. beta-elemene inhibits the proliferation of T24 bladder carcinoma cells through upregulation of the expression of Smad4. Mol Med Rep 7, 513–518, 2013. doi: 10.3892/mmr.2012.1206
   PubMed Web of Science ®Google Scholar
• Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, and Bray F: International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol 67, 519–530, 2015. doi: 10.1016/j.eururo.2014.10.002
   PubMed Web of Science ®Google Scholar
• Medina-Rico M, Ramos HL, Lobo M, Romo J, and Prada JG: Epidemiology of renal cancer in developing countries: review of the literature. Can Urol Assoc J 12, E154–e162, 2017. doi: 10.5489/cuaj.4464
   PubMed Web of Science ®Google Scholar
• Zhan YH, Liu J, Qu XJ, Hou KZ, Wang KF, et al. β-elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/ mTOR signalling pathways. Asian Pac J Cancer Prev 13, 2739–2744, 2012.
   PubMed Web of Science ®Google Scholar
• van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 378, 230–240, 2018. doi: 10.1056/NEJMoa1708618
   PubMed Web of Science ®Google Scholar
• Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354, 34–43, 2006. doi: 10.1056/NEJMoa052985
   PubMed Web of Science ®Google Scholar
• Pilotti S, Oggionni M, Bohm S, Pierotti MA, and Zunino F: ICON3 and chemotherapy for ovarian cancer. Lancet 360, 2087–2088; author reply 2088, 2002.
   PubMed Web of Science ®Google Scholar
• McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334, 1–6, 1996. doi: 10.1056/nejm199601043340101
   PubMed Web of Science ®Google Scholar
• Miller DS, Blessing JA, Krasner CN, Mannel RS, Hanjani P, et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 27, 2686–2691, 2009. doi: 10.1200/jco.2008.19.2963
   PubMed Web of Science ®Google Scholar
• Bell D, Berchuck A, Birrer M, Chien J, Cramer D, et al. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615, 2011. doi: 10.1038/nature10166
   PubMed Web of Science ®Google Scholar
• Li QQ, Lee RX, Liang H, Wang G, Li JM, et al. beta-Elemene enhances susceptibility to cisplatin in resistant ovarian carcinoma cells via downregulation of ERCC-1 and XIAP and inactivation of JNK. Int J Oncol 43, 721–728, 2013. doi: 10.3892/ijo.2013.1996
   PubMed Web of Science ®Google Scholar
• Li X, Wang G, Zhao J, Ding H, Cunningham C, et al. Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. Cell Mol Life Sci 62, 894–904, 2005. doi: 10.1007/s00018-005-5027-1
   PubMed Web of Science ®Google Scholar
• Li QQ, Lee RX, Liang H, Zhong Y, and Reed E: Enhancement of cisplatin-induced apoptosis by beta-elemene in resistant human ovarian cancer cells. Med Oncol 30, 424, 2013. doi: 10.1007/s12032-012-0424-4
   PubMed Web of Science ®Google Scholar
• Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, et al. Exciting new advances in neuro-oncology: The avenue to a cure for malignant glioma. CA Cancer J Clin 60, 166–193, 2010. doi: 10.3322/caac.20069
   PubMed Web of Science ®Google Scholar
• Omuro A, and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. J Am Med Assoc 310, 1842–1850, 2013. doi: 10.1001/jama.2013.280319
   PubMed Web of Science ®Google Scholar
• Shah U, and Morrison T: A review of the symptomatic management of malignant gliomas in adults. J Natl Compr Canc Netw 11, 424–429, 2013.
   PubMed Web of Science ®Google Scholar
• Meyer MA: Malignant gliomas in adults. N Engl J Med 359, 1850; author reply 18502008. doi: 10.1056/NEJMc086380
   PubMed Web of Science ®Google Scholar
• Wu XS, Xie T, Lin J, Fan HZ, Huang-Fu HJ, et al. An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas. J Pharm Pharmacol 61, 1653–1656, 2009. doi: 10.1211/jpp/61.12.0010
   PubMed Web of Science ®Google Scholar
• Zhu T, Zhao Y, Zhang J, Li L, Zou L, et al. β-elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. Int J Oncol 38, 419–426, 2011. doi: 10.3892/ijo.2010.855
   PubMed Web of Science ®Google Scholar
• Zhu T, Xu Y, Dong B, Zhang J, Wei Z, et al. beta-elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor beta and induces sensitization to cisplatin. Oncol Rep 26, 405–413, 2011. doi: 10.3892/or.2011.1276
   PubMed Web of Science ®Google Scholar
• Zhu TZ, Li XM, Luo LH, Song ZQ, Gao X, et al. beta-elemene inhibits stemness, promotes differentiation and impairs chemoresistance to temozolomide in glioblastoma stem-like cells. Int J Oncol 45, 699–709, 2014. doi: 10.3892/ijo.2014.2448
   PubMed Web of Science ®Google Scholar
• Zhu T, Li X, Luo L, Wang X, Li Z, et al. Reversion of malignant phenotypes of human glioblastoma cells by beta-elemene through beta-catenin-mediated regulation of stemness-, differentiation- and epithelial-to-mesenchymal transition-related molecules. J Transl Med 13, 356, 2015. doi: 10.1186/s12967-015-0727-2
   PubMed Web of Science ®Google Scholar
• Liu S, Zhou L, Zhao Y, and Yuan Y: beta-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway. Oncol Rep 34, 943–951, 2015. doi: 10.3892/or.2015.4050
   PubMed Web of Science ®Google Scholar
• Mu L, Wang T, Chen Y, Tang X, Yuan Y, et al. beta-elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway. Int J Oncol 49, 1427–1436, 2016. doi: 10.3892/ijo.2016.3626
   PubMed Web of Science ®Google Scholar
• Zhu TZ, Li XM, Luo LH, Xu YH, Cao P, et al. beta-elemene inhibits proliferation through crosstalk between glia maturation factor beta and extracellular signalregulated kinase 1/2 and impairs drug resistance to temozolomide in glioblastoma cells. Mol Med Rep 10, 1122–1128, 2014. doi: 10.3892/mmr.2014.2273
   PubMed Web of Science ®Google Scholar
• Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136, E359–E386, 2015. doi: 10.1002/ijc.29210
   PubMed Web of Science ®Google Scholar
• Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, et al. Global cancer statistics, 2012. CA Cancer J Clin 65, 87–108, 2015. doi: 10.3322/caac.21262
   PubMed Web of Science ®Google Scholar
• Li J, Yu J, Liu A, and Wang Y: beta-elemene against human lung cancer via up-regulation of P53 protein expression to promote the release of exosome. Lung Cancer 86, 144–150, 2014. doi: 10.1016/j.lungcan.2014.08.015
   PubMed Web of Science ®Google Scholar
• Wu Z, Wang T, Zhang Y, Zheng Z, Yu S, et al. Anticancer effects of beta-elemene with hyperthermia in lung cancer cells. Exp Ther Med 13, 3153–3157, 2017. doi: 10.3892/etm.2017.4350
   PubMed Web of Science ®Google Scholar
• Li LJ, Zhong LF, Jiang LP, Geng CY, Zhu TZ, et al. Lysosomal membrane permeabilization contributes to elemene emulsion-induced apoptosis in A549 cells. Free Radic Res 45, 1232–1240, 2011. doi: 10.3109/10715762.2011.607818
   PubMed Web of Science ®Google Scholar
• Liu J, Hu XJ, Jin B, Qu XJ, Hou KZ, et al. beta-elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells. J Pharm Pharmacol 64, 146–153, 2012. doi: 10.1111/j.2042-7158.2011.01371.x
   PubMed Web of Science ®Google Scholar
• Li L, Xu L, Qu X, Zhao M, Yu P, et al. Cbl-regulated Akt and ERK signals are involved in β-elemene-induced cell apoptosis in lung cancer cells. Mol Med Rep 4, 1243–1246, 2011. doi: 10.3892/mmr.2011.548
   PubMed Web of Science ®Google Scholar
• Zhao S, Wu J, Zheng F, Tang Q, Yang L, et al. beta-elemene inhibited expression of DNA methyltransferase 1 through activation of ERK1/2 and AMPKalpha signalling pathways in human lung cancer cells: the role of Sp1. J Cell Mol Med 19, 630–641, 2015. doi: 10.1111/jcmm.12476
   PubMed Web of Science ®Google Scholar
• Liu Y, Jiang ZY, Zhou YL, Qiu HH, Wang G, et al. beta-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1alpha/ATF6 pathway. Biomed Pharma 93, 490–497, 2017. doi: 10.1016/j.biopha.2017.06.073
   PubMed Web of Science ®Google Scholar
• Zheng F, Tang Q, Zheng XH, Wu J, Huang H, et al. Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer. Exp Mol Med 50, 121, 2018. doi: 10.1038/s12276-018-0146-6
   PubMed Web of Science ®Google Scholar
• Yu X, Xu M, Li N, Li Z, Li H, et al. beta-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer. Biochem Biophys Res Commun 490, 514–520, 2017. doi: 10.1016/j.bbrc.2017.06.071
   PubMed Web of Science ®Google Scholar
• Yao C, Jiang J, Tu Y, Ye S, Du H, et al. beta-elemene reverses the drug resistance of A549/DDP lung cancer cells by activating intracellular redox system, decreasing mitochondrial membrane potential and P-glycoprotein expression, and inducing apoptosis. Thorac Cancer 5, 304–312, 2014. doi: 10.1111/1759-7714.12093
   PubMed Web of Science ®Google Scholar
• Li QQ, Wang G, Huang F, Li JM, Cuff CF, et al. Sensitization of lung cancer cells to cisplatin by beta-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of beta-elemene and its synthetic analogs. Med Oncol 30, 488, 2013. doi: 10.1007/s12032-013-0488-9
   PubMed Web of Science ®Google Scholar
• Li G, Xie B, Li X, Chen Y, Wang Q, et al. Down-regulation of survivin and hypoxia-inducible factor-1 alpha by beta-elemene enhances the radiosensitivity of lung adenocarcinoma xenograft. Cancer Biother Radiopharm 27, 56–64, 2012. doi: 10.1089/cbr.2011.1003
   PubMed Web of Science ®Google Scholar
• Tong E, Xu Y, Li G, Zou K, and Zou L: The effects of β-elemene on the expression of mTOR, HIF-1A, survivin in lung adenocarcinoma A549 cell. Afr J Tradit Complement Altern Med 10, 18–23, 2013.
   PubMedGoogle Scholar
• Zou K, Liu C, Zhang Z, and Zou L: The effect of elemene on lung adenocarcinoma A549 cell radiosensitivity and elucidation of its mechanism. Clinics (Sao Paulo) 70, 556–562, 2015. doi: 10.6061/clinics/2015(08)05
   PubMed Web of Science ®Google Scholar
• Sun YN, Zhang ZY, Zheng YC, Chi F, Jin XY, et al. Comparative efficacy of whole-brain radiotherapy with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma. Curr Oncol 23, 377–382, 2016. doi: 10.3747/co.23.3183
   Web of Science ®Google Scholar
• Jerant AF, Johnson JT, Sheridan CD, and Caffrey TJ: Early detection and treatment of skin cancer. Am Fam Physician 62, 357–356, 381–382, 2000.
   PubMed Web of Science ®Google Scholar
• Tan W, Lu J, Huang M, Li Y, Chen M, et al. Anti-cancer natural products isolated from chinese medicinal herbs. Chin Med 6, 27, 2011. doi: 10.1186/1749-8546-6-27
   PubMed Web of Science ®Google Scholar
• Guadagnolo BA, and Zagars GK: Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol 10, 409–416, 2009. doi: 10.1016/s1470-2045(09)70043-9
   PubMed Web of Science ®Google Scholar
• Lorigan P, Eisen T, and Hauschild A: Systemic therapy for metastatic malignant melanoma–from deeply disappointing to bright future? Exp Dermatol 17, 383–394, 2008. doi: 10.1111/j.1600-0625.2007.00673.x
   PubMed Web of Science ®Google Scholar
• Jahng AW, and Liao SS: Successful palliation with octreotide of a neuroendocrine syndrome from malignant melanoma. J Pain Symptom Manage 32, 191–195, 2006. doi: 10.1016/j.jpainsymman.2006.02.014
   PubMed Web of Science ®Google Scholar
• Bedikian AY: Metastatic uveal melanoma therapy: current options. Int Ophthalmol Clin 46, 151–166, 2006.
   PubMedGoogle Scholar
• Damato B: Does ocular treatment of uveal melanoma influence survival? Br J Cancer 103, 285–290, 2010. doi: 10.1038/sj.bjc.6605765
   PubMed Web of Science ®Google Scholar
• Chen W, Lu Y, Wu J, Gao M, Wang A, et al. Beta-elemene inhibits melanoma growth and metastasis via suppressing vascular endothelial growth factor-mediated angiogenesis. Cancer Chemother Pharmacol 67, 799–808, 2011. doi: 10.1007/s00280-010-1378-x
   PubMed Web of Science ®Google Scholar
• Shi H, Liu L, Liu L, Geng J, Zhou Y, et al. beta-Elemene inhibits the metastasis of B16F10 melanoma cells by downregulation of the expression of uPA, uPAR, MMP-2, and MMP-9. Melanoma Res 24, 99–107, 2014. doi: 10.1097/cmr.0000000000000043
   PubMed Web of Science ®Google Scholar
• Shi H, Liu L, Liu LM, Geng J, and Chen L: Inhibition of tumor growth by beta-elemene through downregulation of the expression of uPA, uPAR, MMP-2, and MMP-9 in a murine intraocular melanoma model. Melanoma Res 25, 15–21, 2015. doi: 10.1097/cmr.0000000000000124
   PubMed Web of Science ®Google Scholar
• Harbeck N, and Gnant M: Breast Cancer. Lancet 389, 1134–1150, 2017. doi: 10.1016/s0140-6736(16)31891-8
   Web of Science ®Google Scholar
• Zhang J, Zhang H, Chen L, Sun DW, Mao C, et al. Beta-elemene reverses chemoresistance of breast cancer via regulating MDR-related microRNA expression. Cell Physiol Biochem 34, 2027–2037, 2014. doi: 10.1159/000366398
   PubMedGoogle Scholar
• Guan C, Liu W, Yue Y, Jin H, Wang X, et al. Inhibitory effect of beta-elemene on human breast cancer cells. Int J Clin Exp Pathol 7, 3948–3956, 2014.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Sun X, Nan N, Cao KX, Ma C, et al. Elemene inhibits the migration and invasion of 4T1 murine breast cancer cells via heparanase. Mol Med Rep 16, 794–800, 2017. doi: 10.3892/mmr.2017.6638
   PubMed Web of Science ®Google Scholar
• Zhang X, Zhang Y, and Li Y: beta-elemene decreases cell invasion by upregulating E-cadherin expression in MCF-7 human breast cancer cells. Oncol Rep 30, 745–750, 2013. doi: 10.3892/or.2013.2519
   PubMed Web of Science ®Google Scholar
• Zhang X, Li Y, Zhang Y, Song J, Wang Q, et al. Beta-elemene blocks epithelial-mesenchymal transition in human breast cancer cell line MCF-7 through Smad3-mediated down-regulation of nuclear transcription factors. PLoS One 8, e58719, 2013. doi: 10.1371/journal.pone.0058719
   PubMed Web of Science ®Google Scholar
• Drabsch Y, and ten Dijke P: TGF-beta signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev 31, 553–568, 2012. doi: 10.1007/s10555-012-9375-7
   PubMed Web of Science ®Google Scholar
• Xu HB, Li L, Fu J, Mao XP, and Xu LZ: Reversion of multidrug resistance in a chemoresistant human breast cancer cell line by beta-elemene. Pharmacology 89, 303–312, 2012. doi: 10.1159/000337178
   PubMed Web of Science ®Google Scholar
• Zhang J, Zhang HD, Yao YF, Zhong SL, Zhao JH, et al. beta-elemene reverses chemoresistance of breast cancer cells by reducing resistance transmission via exosomes. Cell Physiol Biochem 36, 2274–2286, 2015. doi: 10.1159/000430191
   PubMedGoogle Scholar
• Zhang B, Zhang X, Tang B, Zheng P, and Zhang Y: Investigation of elemene-induced reversal of tamoxifen resistance in MCF-7 cells through oestrogen receptor alpha (ERalpha) re-expression. Breast Cancer Res Treat 136, 399–406, 2012. doi: 10.1007/s10549-012-2263-6
   PubMed Web of Science ®Google Scholar
• Harlan LC, and Warren JL: Global survival patterns: potential for cancer control. Lancet 385, 926–928, 2015. doi: 10.1016/s0140-6736(14)62251-0
   PubMed Web of Science ®Google Scholar
• Mao Y, Zhang J, Hou L, and Cui X: The effect of beta-elemene on alpha-tubulin polymerization in human hepatoma HepG2 cells. Chin J Cancer Res 25, 770, 2013. doi: 10.3978/j.issn.1000-9604.2013.12.12
   PubMed Web of Science ®Google Scholar
• Gong M, Liu Y, Zhang J, Gao YJ, Zhai PP, et al. beta-elemene inhibits cell proliferation by regulating the expression and activity of topoisomerases I and IIalpha in human hepatocarcinoma HepG-2 cells. Biomed Res Int 2015, 1–10, 2015. doi: 1155/2015/153987
   Web of Science ®Google Scholar
• Bao F, Qiu J, and Zhang H: Potential role of β-elemene on histone H1 in the H22 ascites hepatoma cell line. Mol Med Rep 6, 185–190, 2012. doi: 10.3892/mmr.2012.891
   PubMed Web of Science ®Google Scholar
• Dai ZJ, Tang W, Lu WF, Gao J, Kang HF, et al. Antiproliferative and apoptotic effects of beta-elemene on human hepatoma HepG2 cells. Cancer Cell Int 13, 27, 2013. doi: 10.1186/1475-2867-13-27
   PubMed Web of Science ®Google Scholar
• Chua MLK, Wee JTS, Hui EP, and Chan ATC: Nasopharyngeal carcinoma. Lancet 387, 1012–1024, 2016. doi: 10.1016/s0140-6736(15)00055-0
   PubMed Web of Science ®Google Scholar
• Lee AW, Ma BB, Ng WT, and Chan AT: Management of nasopharyngeal carcinoma: Current practice and future perspective. J Clin Oncol 33, 3356–3364, 2015. doi: 10.1200/jco.2015.60.9347
   PubMed Web of Science ®Google Scholar
• Wu J, Tang Q, Yang L, Chen Y, Zheng F, et al. Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to beta-elemene-inhibited growth of nasopharyngeal carcinoma cells. Sci Rep 7, 509, 2017. doi: 10.1038/s41598-017-00626-6
   Web of Science ®Google Scholar