Parthenolide suppresses tumor growth in a xenograft model of colorectal cancer cells by inducing mitochondrial dysfunction and apoptosis

Kim,Se-Lim; Trang,Kieu  The Thu; Kim,Seong  Hun; Kim,In  Hee; Lee,Seung  Ok; Lee,Soo  Teik; Kim,Dae  Ghon; Kim,Sang-Wook

doi:10.3892/ijo.2012.1587

Parthenolide suppresses tumor growth in a xenograft model of colorectal cancer cells by inducing mitochondrial dysfunction and apoptosis

Authors:
- Se-Lim Kim
- Kieu The Thu Trang
- Seong Hun Kim
- In Hee Kim
- Seung Ok Lee
- Soo Teik Lee
- Dae Ghon Kim
- Sang-Wook Kim
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Affiliations: Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University, Jeonju 561-712, Republic of Korea
Published online on: August 9, 2012 https://doi.org/10.3892/ijo.2012.1587
Pages: 1547-1553

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Abstract

Parthenolide (PT), a principal active component in medicinal plants, has been used conventionally to treat migraine and inflammation. This component has recently been reported to induce apoptosis in cancer cells, through mitochondrial dysfunction. In the present study, we investigated PT-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members in human colorectal cancer cells. We also investigated the inhibitory effect of PT on tumor growth in xenografts. Using the human colorectal cancer cell lines HT-29, SW620 and LS174T, we demonstrated that treatment of these cancer cells with PT induces apoptosis using MTT, Annexin V assay and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome c release and caspase activation. Moreover, intraperitoneal injection of PT showed significant inhibition of tumor growth, angiogenesis in the xenograft model. These results demonstrate that PT exhibits anti-cancer activity in human colorectal cancer in vitro and in vivo. These findings may also provide a novel approach for the treatment of colorectal cancer.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar
2	Meyerhardt JA and Mayer RJ: Systemic therapy for colorectal cancer. N Engl J Med. 352:476–487. 2005. View Article : Google Scholar : PubMed/NCBI
3	Tebbutt NC, Cattell E, Midgley R, Cunningham D and Kerr D: Systemic treatment of colorectal cancer. Eur J Cancer. 38:1000–1015. 2002. View Article : Google Scholar : PubMed/NCBI
4	Gusella M, Frigo AC, Bolzonella C, et al: Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer. Br J Cancer. 100:1549–1557. 2009. View Article : Google Scholar : PubMed/NCBI
5	Raymond E, Faivre S, Chaney S, Woynarowski J and Cvitkovic E: Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 1:227–235. 2002.
6	Knight DW: Feverfew: chemistry and biological activity. Nat Prod Rep. 12:271–276. 1995. View Article : Google Scholar : PubMed/NCBI
7	Murphy JJ, Heptinstall S and Mitchell JR: Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet. 2:189–192. 1988. View Article : Google Scholar : PubMed/NCBI
8	Hehner SP, Heinrich M, Bork PM, et al: Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta. J Biol Chem. 273:1288–1297. 1998. View Article : Google Scholar : PubMed/NCBI
9	Lyss G, Knorre A, Schmidt TJ, Pahl HL and Merfort I: The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem. 273:33508–33516. 1998. View Article : Google Scholar : PubMed/NCBI
10	Zhang S, Ong CN and Shen HM: Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 208:143–153. 2004. View Article : Google Scholar : PubMed/NCBI
11	Wen J, You KR, Lee SY, Song CH and Kim DG: Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide J Biol Chem. 277:38954–38964. 2002.PubMed/NCBI
12	Pajak B, Gajkowska B and Orzechowski A: Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells. Folia Histochem Cytobiol. 46:129–135. 2008. View Article : Google Scholar : PubMed/NCBI
13	Mathema VB, Koh YS, Thakuri BC and Sillanpaa M: Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities. Inflammation. 35:560–565. 2012. View Article : Google Scholar : PubMed/NCBI
14	Zhao LJ, Xu YH and Li Y: Effect of parthenolide on proliferation and apoptosis in gastric cancer cell line SGC7901. J Dig Dis. 10:172–180. 2009. View Article : Google Scholar
15	Zhang S, Ong CN and Shen HM: Involvement of proapoptotic Bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis. Cancer Lett. 211:175–188. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chen YC, Shen SC, Lee WR, et al: Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. Biochem Pharmacol. 64:1713–1724. 2002. View Article : Google Scholar : PubMed/NCBI
17	Grutter MG: Caspases: key players in programmed cell death. Curr Opin Struct Biol. 10:649–655. 2000. View Article : Google Scholar : PubMed/NCBI
18	Yang JC and Cortopassi GA: Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome c. Free Radic Biol Med. 24:624–631. 1998. View Article : Google Scholar : PubMed/NCBI
19	Tacchini L, De Ponti C, Matteucci E, Follis R and Desiderio MA: Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines. Carcinogenesis. 25:2089–2100. 2004. View Article : Google Scholar
20	Dai Y, Guzman ML, Chen S, et al: The NF (nuclear factor)-kappaB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol. 151:70–83. 2010. View Article : Google Scholar
21	Nakshatri H, Rice SE and Bhat-Nakshatri P: Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene. 23:7330–7344. 2004. View Article : Google Scholar
22	Carlisi D, D’Anneo A, Angileri L, et al: Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol. 226:1632–1641. 2011. View Article : Google Scholar
23	Chen KF, Tai WT, Liu TH, et al: Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res. 16:5189–5199. 2010. View Article : Google Scholar : PubMed/NCBI
24	Wu C, Chen F, Rushing JW, et al: Antiproliferative activities of parthenolide and golden feverfew extract against three human cancer cell lines. J Med Food. 9:55–61. 2006. View Article : Google Scholar : PubMed/NCBI
25	Fernandes-Alnemri T, Litwack G and Alnemri ES: CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem. 269:30761–30764. 1994.PubMed/NCBI
26	Mehmet H: Caspases find a new place to hide. Nature. 403:29–30. 2000. View Article : Google Scholar : PubMed/NCBI
27	Yang E and Korsmeyer SJ: Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood. 88:386–401. 1996.PubMed/NCBI
28	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
29	Reed JC: Double identity for proteins of the Bcl-2 family. Nature. 387:773–776. 1997. View Article : Google Scholar : PubMed/NCBI
30	Adams JM and Cory S: The Bcl-2 protein family: arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
31	Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI
32	Terrones O, Antonsson B, Yamaguchi H, et al: Lipidic pore formation by the concerted action of proapoptotic BAX and tBID. J Biol Chem. 279:30081–30091. 2004. View Article : Google Scholar : PubMed/NCBI
33	Van Mau N, Kajava AV, Bonfils C, Martinou JC and Harricane MC: Interactions of Bax and tBid with lipid monolayers. J Membr Biol. 207:1–9. 2005.PubMed/NCBI
34	Coutts AS and La Thangue N: The p53 response during DNA damage: impact of transcriptional cofactors. Biochem Soc Symp. 181–189. 2006.PubMed/NCBI
35	Kroemer G and Reed JC: Mitochondrial control of cell death. Nat Med. 6:513–519. 2000. View Article : Google Scholar
36	Borner C: The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol. 39:615–647. 2003. View Article : Google Scholar : PubMed/NCBI
37	Ferrara N, Hillan KJ, Gerber HP and Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 3:391–400. 2004. View Article : Google Scholar : PubMed/NCBI
38	Huang S, Pettaway CA, Uehara H, Bucana CD and Fidler IJ: Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 20:4188–4197. 2001. View Article : Google Scholar : PubMed/NCBI
39	Oka D, Nishimura K, Shiba M, et al: Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB. Int J Cancer. 120:2576–2581. 2007. View Article : Google Scholar : PubMed/NCBI
40	Weng SX, Sui MH, Chen S, et al: Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest. J Zhejiang Univ Sci B. 10:528–535. 2009. View Article : Google Scholar : PubMed/NCBI