Pien Tze Huang inhibits the proliferation, and induces the apoptosis and differentiation of colorectal cancer stem cells via suppression of the Notch1 pathway

Qi,Fei; Wei,Lihui; Shen,Aling; Chen,Youqin; Lin,Jiumao; Chu,Jianfeng; Cai,Qiaoyan; Pan,Jie; Peng,Jun

doi:10.3892/or.2015.4378

Pien Tze Huang inhibits the proliferation, and induces the apoptosis and differentiation of colorectal cancer stem cells via suppression of the Notch1 pathway

Authors:
- Fei Qi
- Lihui Wei
- Aling Shen
- Youqin Chen
- Jiumao Lin
- Jianfeng Chu
- Qiaoyan Cai
- Jie Pan
- Jun Peng
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Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd., Shangjie, Zhangzhou, Fujian 363000, P.R. China
Published online on: November 2, 2015 https://doi.org/10.3892/or.2015.4378
Pages: 511-517

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Abstract

Cancer stem cells (CSCs) possess properties of continuous self-renewal, multi-directional differentiation and natural chemoresistance, leading to the initiation, progression and relapse of cancer. The characteristics of CSCs are strongly associated with multiple cellular pathways such as Notch1 signaling. Therefore, targeting CSCs via suppressing the Notch1 pathway might represent a promising strategy for cancer treatment. The well‑known traditional Chinese medicine (TCM) formula Pien Tze Huang (PZH) has long been used as an alternative remedy for various cancers including colorectal cancer (CRC). We previously reported that PZH contains a broad range of anticancer activities including an inhibitory effect on CSCs. To further elucidate the mode of action of PZH, in this study we isolated the stem‑like side population (SP) from the human CRC SW480 cell line to investigate its effect on CSCs as well as the possible molecular mechanisms. As compared with non‑SP cells, the isolated SW480 SP cells displayed stronger capacities of spheroid formation in vitro and tumorigenicity in vivo, demonstrating the stem cell‑like features of SP cells. However, PZH treatment significantly decreased the percentage of SP cells in a dose‑dependent manner. In addition, PZH significantly and does‑dependently inhibited the viability and promoted the apoptosis and differentiation of the isolated SW480 SP cells. Moreover, PZH treatment profoundly reduced the mRNA and protein expression of Notch1 and Hes1 in the SP cells. Our findings suggest that PZH negatively modulates the characteristics of CSCs through suppression of the Notch1 signaling pathway.

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1	Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar : PubMed/NCBI
2	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
3	Dalerba P, Cho RW and Clarke MF: Cancer stem cells: Models and concepts. Annu Rev Med. 58:267–284. 2007. View Article : Google Scholar
4	Costea DE, Tsinkalovsky O, Vintermyr OK, Johannessen AC and Mackenzie IC: Cancer stem cells - new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Dis. 12:443–454. 2006. View Article : Google Scholar : PubMed/NCBI
5	Locke M, Heywood M, Fawell S and Mackenzie IC: Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res. 65:8944–8950. 2005. View Article : Google Scholar : PubMed/NCBI
6	Takebe N, Harris PJ, Warren RQ and Ivy SP: Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 8:97–106. 2011. View Article : Google Scholar
7	Bolós V, Blanco M, Medina V, Aparicio G, Díaz-Prado S and Grande E: Notch signalling in cancer stem cells. Clin Transl Oncol. 11:11–19. 2009. View Article : Google Scholar : PubMed/NCBI
8	Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P and Wicha MS: Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66:6063–6071. 2006. View Article : Google Scholar : PubMed/NCBI
9	Noggle SA, Weiler D and Condie BG: Notch signaling is inactive but inducible in human embryonic stem cells. Stem Cells. 24:1646–1653. 2006. View Article : Google Scholar : PubMed/NCBI
10	Miyamoto S and Rosenberg DW: role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci. 102:1938–1942. 2011. View Article : Google Scholar : PubMed/NCBI
11	Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: Cell fate control and signal integration in development. Science. 284:770–776. 1999. View Article : Google Scholar : PubMed/NCBI
12	Ohishi K, Varnum-Finney B, Flowers D, Anasetti C, Myerson D and Bernstein ID: Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1. blood. 95:2847–2854. 2000.PubMed/NCBI
13	Bolós V, Grego-bessa J and de la Pompa JL: Notch signaling in development and cancer. Endocr Rev. 28:339–363. 2007. View Article : Google Scholar : PubMed/NCBI
14	Hansson EM, Lendahl U and Chapman G: Notch signaling in development and disease. Semin Cancer biol. 14:320–328. 2004. View Article : Google Scholar : PubMed/NCBI
15	Iso T, Kedes L and Hamamori Y: HES and HERP families: Multiple effectors of the Notch signaling pathway. J Cell Physiol. 194:237–255. 2003. View Article : Google Scholar : PubMed/NCBI
16	Zhang Y, Li B, Ji ZZ and Zheng PS: Notch1 regulates the growth of human colon cancers. Cancer. 116:5207–5218. 2010. View Article : Google Scholar : PubMed/NCBI
17	Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, Lockwood G, Gallinger S and Egan SE: Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 33:1223–1229. 2008.PubMed/NCBI
18	Miele L, Golde T and Osborne B: Notch signaling in cancer. Curr Mol Med. 6:905–918. 2006. View Article : Google Scholar : PubMed/NCBI
19	Qiu M, Peng Q, Jiang I, Carroll C, Han G, Rymer I, Lippincott J, Zachwieja J, Gajiwala K, Kraynov E, et al: Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett. 328:261–270. 2013. View Article : Google Scholar
20	Sharma A, Paranjape AN, Rangarajan A and Dighe RR: A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells. Mol Cancer Ther. 11:77–86. 2012. View Article : Google Scholar
21	Wang J, Wang C, Meng Q, Li S, Sun X, Bo Y and Yao W: sirNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth. Mol biol rep. 39:2497–2503. 2012. View Article : Google Scholar
22	Fre S, Huyghe M, Mourikis P, Robine S, Louvard D and Artavanis-Tsakonas S: Notch signals control the fate of immature progenitor cells in the intestine. Nature. 435:964–968. 2005. View Article : Google Scholar : PubMed/NCBI
23	Ward RJ and Dirks PB: Cancer stem cells: At the headwaters of tumor development. Annu Rev Pathol. 2:175–189. 2007. View Article : Google Scholar : PubMed/NCBI
24	Efferth T: Stem cells, cancer stem-like cells, and natural products. Planta Med. 78:935–942. 2012. View Article : Google Scholar : PubMed/NCBI
25	Lin JM, Wei LH, Chen YQ, Liu XX, Hong ZF, Sferra TJ and Peng J: Pien Tze Huang induced apoptosis in human colon cancer HT-29 cells is associated with regulation of the bcl-2 family and activation of caspase 3. Chin J Integr Med. 17:685–690. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zhuang Q, Hong F, Shen A, Zheng L, Zeng J, Lin W, Chen Y, Sferra TJ, Hong Z and Peng J: Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model. Int J Oncol. 40:1569–1574. 2012.PubMed/NCBI
27	Shen AL, Hong F, Liu LY, Lin JM, Zhuang QC, Hong ZF and Peng J: Effects of Pien Tze Huang on angiogenesis in vivo and in vitro. Chin J Integr Med. 18:431–436. 2012. View Article : Google Scholar : PubMed/NCBI
28	Shen A, Hong F, Liu L, Lin J, Wei L, Cai Q, Hong Z and Peng J: Pien Tze Huang inhibits the proliferation of human colon carcinoma cells by arresting G1/S cell cycle progression. Oncol Lett. 4:767–770. 2012.PubMed/NCBI
29	Shen A, Chen Y, Hong F, Lin J, Wei L, Hong Z, Sferra TJ and Peng J: Pien Tze Huang suppresses IL-6-inducible STAT3 activation in human colon carcinoma cells through induction of SOCS3. Oncol Rep. 28:2125–2130. 2012.PubMed/NCBI
30	Shen A, Lin J, Chen Y, Lin W, Liu L, Hong Z, Sferra TJ and Peng J: Pien Tze Huang inhibits tumor angiogenesis in a mouse model of colorectal cancer via suppression of multiple cellular pathways. Oncol Rep. 30:1701–1706. 2013.PubMed/NCBI
31	Huang M, Zhao H, Xu W, Chu K, Hong Z, Peng J and Chen L: Rapid simultaneous determination of twelve major components in Pien Tze Huang by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. J Sep Sci. 36:3866–3873. 2013. View Article : Google Scholar : PubMed/NCBI
32	Chen H, Shen A, Zhang Y, Chen Y, Lin J, Lin W, Sferra T and Peng J: Pien Tze Huang inhibits hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells through suppression of the HIF-1 pathway. Exp Ther Med. 7:1237–1242. 2014.PubMed/NCBI
33	Shen A, Chen H, Chen Y, Lin J, Lin W, Liu L, Sferra TJ and Peng J: Pien Tze Huang overcomes multidrug resistance and epithelial-mesenchymal transition in human colorectal carcinoma cells via suppression of TGF-β pathway. Evid based Complement Alternat Med. 2014:6794362014. View Article : Google Scholar
34	Lin W, Zhuang Q, Zheng L, Cao Z, Shen A, Li Q, Fu C, Feng J and Peng J: Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer. Oncol Rep. 33:1922–1928. 2015.PubMed/NCBI
35	Chen H, Feng J, Zhang Y, Shen A, Chen Y, Lin J, Lin W, Sferra TJ and Peng J: Pien Tze Huang inhibits hypoxia-induced angiogenesis via HIF-1 α/VEGF-A pathway in colorectal cancer. Evid based Complement Alternat Med. 2015:4542792015. View Article : Google Scholar
36	Shen A, Lin W, Chen Y, Liu L, Chen H, Zhuang Q, Lin J, Sferra TJ and Peng J: Pien Tze Huang inhibits metastasis of human colorectal carcinoma cells via modulation of TGF-β1/ZEb/mir-200 signaling network. Int J Oncol. 46:685–690. 2015.
37	Wei L, Chen P, Chen Y, Shen A, Chen H, Lin W, Hong Z, Sferra TJ and Peng J: Pien Tze Huang suppresses the stem-like side population in colorectal cancer cells. Mol Med Rep. 9:261–266. 2014.
38	Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI
39	Markowitz SD and Bertagnolli MM: Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 361:2449–2460. 2009. View Article : Google Scholar : PubMed/NCBI
40	Longley DB, Allen WL and Johnston PG: Drug resistance, predictive markers and pharmacogenomics in colorectal cancer. biochim biophys Acta. 1766:184–196. 2006.PubMed/NCBI
41	Golebiewska A, Brons NH, Bjerkvig R and Niclou SP: Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell. 8:136–147. 2011. View Article : Google Scholar : PubMed/NCBI
42	Scharenberg CW, Harkey MA and Torok-Storb B: The AbCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. blood. 99:507–512. 2002. View Article : Google Scholar : PubMed/NCBI
43	Nicolis SK: Cancer stem cells and 'stemness' genes in neuro-oncology. Neurobiol Dis. 25:217–229. 2007. View Article : Google Scholar
44	Pastrana E, Silva-Vargas V and Doetsch F: Eyes wide open: A critical review of sphere-formation as an assay for stem cells. Cell Stem Cell. 8:486–498. 2011. View Article : Google Scholar : PubMed/NCBI