13,14‑bis(cis‑3,5‑dimethyl‑1‑piperazinyl)‑β‑elemene, a novel β‑elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells

Ding,Xiao‑Fei; Shen,Mao; Xu,Li‑Ying; Dong,Jin‑Hua; Chen,Guang

doi:10.3892/ol.2013.1213

May 2013 Volume 5 Issue 5

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May 2013 Volume 5 Issue 5

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Article

13,14‑bis(cis‑3,5‑dimethyl‑1‑piperazinyl)‑β‑elemene, a novel β‑elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells

Authors:
- Xiao‑Fei Ding
- Mao Shen
- Li‑Ying Xu
- Jin‑Hua Dong
- Guang Chen
View Affiliations / Copyright

Affiliations: School of Medicine, Taizhou College, Taizhou, Zhejiang 318000, P.R. China, School of Pharmaceutical and Chemical Engineering, Taizhou College, Taizhou, Zhejiang 318000, P.R. China, Key Laboratory of Structure‑Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China
Pages: 1554-1558
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Published online on: February 27, 2013

https://doi.org/10.3892/ol.2013.1213
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Abstract

Elemene has been approved for the treatment of advanced cancer in China, however, it inhibits cell growth only at high concentrations and is an essential oil with poor water solubility and stability. The discovery of new β‑elemene derivatives is of increasing interest. We recently reported that the compound 13,14‑bis(cis‑3,5‑dimethyl-1-piperazinyl)‑β‑elemene (IIi), a novel β‑elemene derivative with a cis‑2,6‑dimethylpiperazine substitution, is a potent agent for inhibiting the proliferation of SGC‑7901 and HeLa cells. In the present study, we further verified that IIi is cytotoxic to a wide spectrum of human cancer cells in culture, including those of breast, ovarian, lung, gastric, hepatocellular and colon cancer, as well as leukemia cell lines, with an average IC50 of 3.44 µmol/l. Notably, IIi showed significant cytotoxicity in two multidrug‑resistant (MDR) cell lines, with an average resistance factor (RF) of 1.66. Moreover, in mice with S‑180 sarcoma xenografts, the intraperitoneal administration of IIi inhibited tumor growth. The immunoblotting study showed that treatment with IIi decreases phosphorylated p70S6K1 and 4EBP1 levels in the human breast cancer MCF‑7 and MDA‑MB‑468 cells. In the MCF‑7 cells, IIi also significantly increased the expression of cleaved LC3. This indicated that IIi inhibits mTOR activity and induces autophagy. The mTOR inhibitory function and the potent antitumor activity, taken together with the appreciable anti‑multidrug resistance action, shows IIi to be a novel potential antitumor agent, which merits further research and development.

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1	World Health Organization: Programmes and projects: Cancer: Breast Cancer Awareness Month in October. http://www.who.int/cancer/events/breast_cancer_month/en/index.html. Accessed October 31, 2011.
2	National Cancer Institute: Cancer statistics: SEER stat fact sheets, breast. http://seer.cancer.gov/statfacts/html/breast.html. Accessed April 5, 2011.
3	Guo YT: Isolation and identification of elemene from the essential oil of Curcuma wenyujin. Zhong Yao Tong Bao. 8(31)1983.(In Chinese).
4	Tan P, Zhong W and Cai W: Clinical study on treatment of 40 cases of malignant brain tumor by elemene emulsion injection. Zhongguo Zhong Xi Yi Jie He Za Zhi. 20:645–648. 2000.(In Chinese).
5	Peng X, Zhao Y, Liang X, et al: Assessing the quality of RCTs on the effect of beta-elemene, one ingredient of a Chinese herb, against malignant tumors. Contemp Clin Trials. 27:70–82. 2006. View Article : Google Scholar : PubMed/NCBI
6	Tao L, Zhou L, Zheng L and Yao M: Elemene displays anti-cancer ability on laryngeal cancer cells in vitro and in vivo. Cancer Chemother Pharmacol. 58:24–34. 2006. View Article : Google Scholar : PubMed/NCBI
7	Wang J, Zhang H and Sun Y: 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.(In Chinese).
8	Xu L, Tao S, Wang X, et al: The synthesis and anti-proliferative effects of beta-elemene derivatives with mTOR inhibition activity. Bioorg Med Chem. 14:5351–5356. 2006. View Article : Google Scholar : PubMed/NCBI
9	Carew JS, Kelly KR and Nawrocki ST: Autophagy as a target for cancer therapy: new developments. Cancer Manag Res. 4:357–365. 2012.
10	Liu J, Hu XJ, Jin B, Qu XJ, Hou KZ and Liu YP: β-Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells. J Pharm Pharmacol. 64:146–153. 2012.
11	Butler MS: The role of natural product chemistry in drug discovery. J Nat Prod. 67:2141–2153. 2004. View Article : Google Scholar : PubMed/NCBI
12	Qing C, Zhang JS and Ding J: In vitro cytotoxicity of salvicine, a novel diterpenoid quinone. Zhongguo Yao Li Xue Bao. 20:297–302. 1999.PubMed/NCBI
13	Kollmannsberger C, Mross K, Jakob A, Kanz L and Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 56:1–12. 1999. View Article : Google Scholar : PubMed/NCBI
14	Wani MC, Taylor HL, Wall ME, Coggon P and McPhail AT: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 93:2325–2327. 1971. View Article : Google Scholar : PubMed/NCBI
15	Ma XM and Blenis J: Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 10:307–318. 2009. View Article : Google Scholar : PubMed/NCBI
16	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007. View Article : Google Scholar
17	Hudes G, Carducci M, Tomczak P, et al: Global ARCC Trial: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 356:2271–2281. 2007. View Article : Google Scholar
18	Motzer RJ, Escudier B, Oudard S, et al RECORD-1 Study Group: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 372:449–456. 2008. View Article : Google Scholar : PubMed/NCBI
19	Wan X and Helman LJ: The biology behind mTOR inhibition in sarcoma. Oncologist. 12:1007–1018. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

13,14‑bis(cis‑3,5‑dimethyl‑1‑piperazinyl)‑β‑elemene, a novel β‑elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells

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