Extract of Caulis Spatholobi, a novel blocker targeting tumor cell‑induced platelet aggregation, inhibits breast cancer metastasis

Chen,Xi; Li,Qi; Kan,Xiao‑Xi; Wang,Ya‑Jie; Li,Yu‑Jie; Yang,Qing; Xiao,Hong‑Bin; Chen,Ying; Weng,Xiao‑Gang; Cai,Wei‑Yan; Zhu,Xiao‑Xin

doi:10.3892/or.2016.5184

Extract of Caulis Spatholobi, a novel blocker targeting tumor cell‑induced platelet aggregation, inhibits breast cancer metastasis

Authors:
- Xi Chen
- Qi Li
- Xiao‑Xi Kan
- Ya‑Jie Wang
- Yu‑Jie Li
- Qing Yang
- Hong‑Bin Xiao
- Ying Chen
- Xiao‑Gang Weng
- Wei‑Yan Cai
- Xiao‑Xin Zhu
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Affiliations: Capital Medical University School of Traditional Chinese Medicine, Beijing 100069, P.R. China, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China, Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, P.R. China
Published online on: October 19, 2016 https://doi.org/10.3892/or.2016.5184
Pages: 3215-3224

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Abstract

Metastasis of breast cancer is the vital step for malignant progression. During such a process, hematogenous metastasis is an indispensable approach for the dissemination of cancer cells. A platelet, contributes to hypercoagulable state, and is also identified the crucial factor in the coagulation system for supporting metastasis. Therefore, the relationship of a platelet and a tumor cell plays a critical role in tumor cell metastasis. Consequently, inhibiting tumor cell‑induced platelet aggregation (TCIPA) is recongnized as a crucial target on suppression of tumor metastasis such as aspirin (ASA). Under such circumstance, here we report that, through dissociating the tumor‑platelet (T‑P) complex, 80% ethanol extracts of Caulis Spatholobi (SET) successfully alleviated the hypercoagulation state, thereby reducing tumor metastasis and improving the prospects of survival in breast cancer cell model. Through MTT and anti‑aggregation assay stimulated by ADP, we detected the optimum treatment time and the optimum dose of SET. By using confocal microscopy, we observed that SET can strongly block the formation of T‑P complex in vitro. The result was further quantified and confirmed by the FACS analysis. The fluorescent value of T‑P complex was obviously decreased in the drug‑treated groups. In vivo, 4T1 cells were injected through the mouse tail vein for dynamic visualization by small animal imaging system. The metastatic intensity was quantified and the survival curve was analyzed. Additionally, general observation and hematoxylin and eosin (H&E) staining of lung tissue was performed. SET exerted an obvious effect on the inhibition of metastasis and increasing the survival rate of mice. For the molecular mechanism study of anti‑TCIPA, zymography and RT‑PCR assay preliminarily revealed the molecular mechanism of SET in the regulation of P‑T interaction. Collectively, through drug efficacy identification and pharmacological revealing, we have obtained a promising candidate for the interference of breast metastasis by suppressing TCIPA, which will be beneficial for clinical cancer treatment.

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1	DeSantis CE, Fedewa SA, Sauer A Goding, Kramer JL, Smith RA and Jemal A: Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. 66:31–42. 2016. View Article : Google Scholar : PubMed/NCBI
2	Baselga J, Cortés J, Kim S-B, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, et al: CLEOPATRA Study Group: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 366:109–119. 2012. View Article : Google Scholar : PubMed/NCBI
3	Wood SL, Pernemalm M, Crosbie PA and Whetton AD: The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 40:558–566. 2014. View Article : Google Scholar : PubMed/NCBI
4	Johnson SA: The Circulating Platelet. Elsevier; New York, NY: 2012, View Article : Google Scholar
5	Byzova TV, Kerr ΒΑ, Feng W and McCabe P: Platelets and the tumor cell microenvironment. Blood. 122:SCI-32-SCI-32. 2013.
6	Riedl J, Pabinger I and Ay C: Platelets in cancer and thrombosis. Hamostaseologie. 34:54–62. 2014. View Article : Google Scholar : PubMed/NCBI
7	Li N: Platelets in cancer metastasis: To help the ‘villain’ to do evil. Int J Cancer. 138:2078–2087. 2015. View Article : Google Scholar : PubMed/NCBI
8	Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI
9	Goubran HA, Burnouf T, Radosevic M and El-Ekiaby M: The platelet-cancer loop. Eur J Intern Med. 24:393–400. 2013. View Article : Google Scholar : PubMed/NCBI
10	Goubran HA, Stakiw J, Radosevic M and Burnouf T: Platelet-cancer interactions. Semin Thromb Hemost. 40:296–305. 2014. View Article : Google Scholar : PubMed/NCBI
11	Stockert JC, Blázquez-Castro A, Cañete M, Horobin RW and Villanueva A: MTT assay for cell viability: Intracellular localization of the formazan product is in lipid droplets. Acta Histochem. 114:785–796. 2012. View Article : Google Scholar : PubMed/NCBI
12	Bentz J, O'Connor MP, Bednarczyk D, Coleman J, Lee C, Palm J, Pak YA, Perloff ES, Reyner E, Balimane P, et al: Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: Implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos. 41:1347–1366. 2013. View Article : Google Scholar : PubMed/NCBI
13	Frenette PS, Johnson RC, Hynes RO and Wagner DD: Platelets roll on stimulated endothelium in vivo: An interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA. 92:7450–7454. 1995. View Article : Google Scholar : PubMed/NCBI
14	Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Bañuelos C, Hernández-Antolín R, Escaned J, Moreno R, Alfonso F, et al: High clopidogrel loading dose during coronary stenting: Effects on drug response and interindividual variability. Eur Heart J. 25:1903–1910. 2004. View Article : Google Scholar : PubMed/NCBI
15	Shou L-M, Zhang Q-Y, Li W, Xie X, Chen K, Lian L, Li ZY, Gong FR, Dai KS, Mao YX, et al: Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of α2 integrin. Oncol Rep. 30:1059–1066. 2013.PubMed/NCBI
16	Labelle M, Begum S and Hynes RO: Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci USA. 111:E3053–E3061. 2014. View Article : Google Scholar : PubMed/NCBI
17	Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, et al: Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 148:259–272. 2012. View Article : Google Scholar : PubMed/NCBI
18	Medina C, Harmon S, Inkielewicz I, Santos-Martinez MJ, Jones M, Cantwell P, Bazou D, Ledwidge M, Radomski MW and Gilmer JF: Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin. Br J Pharmacol. 166:938–949. 2012. View Article : Google Scholar : PubMed/NCBI
19	van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, et al: Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: Investigation of minimal residual disease in acute leukemia. Leukemia. 13:1901–1928. 1999. View Article : Google Scholar : PubMed/NCBI
20	Liu T, Tang H, Lang Y, Liu M and Li X: MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett. 273:233–242. 2009. View Article : Google Scholar : PubMed/NCBI
21	Li M, Xing S, Zhang H, Shang S, Li X, Ren B, Li G, Chang X, Li Y and Li W: A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment. Oncol Rep. 35:1329–1339. 2016.PubMed/NCBI
22	Gay LJ and Felding-Habermann B: Contribution of platelets to tumour metastasis. Nat Rev Cancer. 11:123–134. 2011. View Article : Google Scholar : PubMed/NCBI
23	Sørensen HT, Mellemkjaer L, Steffensen FH, Olsen JH and Nielsen GL: The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 338:1169–1173. 1998. View Article : Google Scholar : PubMed/NCBI
24	Donati MB, Gambacorti-Passerini C, Casali B, Falanga A, Vannotti P, Fossati G, Semeraro N and Gordon SG: Cancer procoagulant in human tumor cells: Evidence from melanoma patients. Cancer Res. 46:6471–6474. 1986.PubMed/NCBI
25	Kannagi R: Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J. 14:577–584. 1997. View Article : Google Scholar : PubMed/NCBI
26	Gasic GJ, Gasic TB, Galanti N, Johnson T and Murphy S: Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer. 11:704–718. 1973. View Article : Google Scholar : PubMed/NCBI
27	Falanga A: Thrombophilia in cancer. Semin Thromb Hemost. 31:104–110. 2005. View Article : Google Scholar : PubMed/NCBI
28	Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW and Mehta Z: Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers during randomised controlled trials. Lancet. 379:1591–1601. 2012. View Article : Google Scholar : PubMed/NCBI
29	Mitrugno A, Williams D, Kerrigan SW and Moran N: A novel and essential role for FcγRIIa in cancer cell-induced platelet activation. Blood. 123:249–260. 2014. View Article : Google Scholar : PubMed/NCBI
30	Patrignani P, Filabozzi P and Patrono C: Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 69:1366–1372. 1982. View Article : Google Scholar : PubMed/NCBI
31	Hankey GJ and Eikelboom JW: Aspirin resistance. Lancet. 367:606–617. 2006. View Article : Google Scholar : PubMed/NCBI
32	Wagner H, Bauer R, Melchart D, Xiao P-G and Staudinger A: Caulis Spatholobi-JixuetengChromatographic Fingerprint Analysis of Herbal Medicines Volume III. 3. 1st. Springer; Switzerland: pp. 235–242. 2014
33	Yan LG, Ruan JS, Zhang L, Fan FT, Zhang F, Wang AY, Zheng SZ, Zeng L, Li WL and Lu Y: Effect of aqueous extracts of several kinds of herbs on human platelet aggregation and expression of P-selectin in vitro. Chin J Integr Med. 21:286–290. 2015. View Article : Google Scholar : PubMed/NCBI
34	Liu B, Liu J, Chen J, Zhu D, Zhou H and Wang X: A study on anticancer activity of Caulis Spatholobi extract on human osteosarcoma Saos-2 cells. Afr J Tradit Complement Altern Medicines. 10:256–260. 2013. View Article : Google Scholar