Effect and Mechanism of Hydroxyapatite Nanoparticle on Hepatocellular Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Guanglian ¹ , YANG Zhiqi ² , SUN Zhengang ² , WANG Shuai ² , XIA Xigang. ²

1.Medical School of Yangtze University, Jingzhou 434020, Hubei Province, China;;
2.Department of General Surgery, Jingzhou Center Hospital, Jingzhou 434020, Hubei Province, China;

Corresponding author：

Keywords：

Hepatoocellular carcinoma; Transcatheter arterial chemoembolization; Hydroxyapatite nanoparticle; Effect; Mechanism

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ObjectiveTo explore the effect of hydroxyapatite nanoparticle (nHAP) on hepatocellular carcinoma (HCC) and its mechanisms. MethodsThe literatures about the effect of nHAP on HCC were reviewed and summarized. ResultsAs a new nanoparticle, nHAP could suppress the DNA synthesis and subsequent division and proliferation of HCC cells through the inhibition of proliferating cell nuclear antigen (PCNA) and telomerase gene expression and increase of intracellular Ca2+. Moreover, nHAP was able to suppress the differentiation and metastases of HCC cells through the effect on the expressions of Paxillin and P130cas and the decrease of expressions of multiple drug resistance gene protein, microvessel density, and vascular endothelial growth factor. Finally, nHAP induced the apoptosis of HCC tumor cells by the regulation of bcl-2 and bax protein expressions. The combined use of nHAP and chemoembolization drugs could enhance the efficacy, prolong drug duration and reduce toxicity. ConclusionnHAP can inhibit the division, proliferation, differentiation, and metastases, and promote the apoptosis of HCC cells and combined use with chemoembolization drugs can enhance the efficacy and reduce toxicity.

Citation： WANG Guanglian,YANG Zhiqi,SUN Zhengang,WANG Shuai,XIA Xigang.. Effect and Mechanism of Hydroxyapatite Nanoparticle on Hepatocellular Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(9): 1017-1020. doi: Copy

1.	Hu J, Liu ZS, Tang SL, et al. Effect of hydroxyapatite nanoparticles on the growth and p53/cMyc protein expression of implanted hepatic VX2 tumor in rabbits by intravenous injection [J]. World J Gastroenterol, 2007, 13(20): 27982802.
2.	Baumann S, Fas SC, Giaisi M, et al. Wogonin preferentially kills malignant lymphocytes and suppresses Tcell tumor growth by inducing PLC gamma1 and Ca2+dependent apoptosis [J]. Blood, 2008, 111(4): 23542363.
3.	Li G, Dong S, Qu J, et al. Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumor necrosis factoralpha in chemotherapy of multidrug resistant hepatocellular carcinoma [J]. Liver Int, 2010, 30(4): 585592.
4.	关键, 胡道予, 孙振纲, 等. 经动脉灌注纳米微粒治疗兔肝VX2肿瘤的实验研究 [J]. 放射学实践, 2007, 22(8): 786789.
5.	Wang A, Yin H, Li D, et al. Effects of organic modifiers on the sizecontrolled synthesis of hydroxyapatite nanorods [J]. Appl Surf Sci, 2007, 253(6): 33113316.
6.	Wang A, Yin H, Li D, et al. Sizecontrolled synthesis of hydroxyapatite nanorods in the presence of organic modifiers [J]. Mater Lett, 2007, 61(10): 20842088.
7.	Saha SK, Banerjee A, Bancrjee, et al. Synthesis of nanocrystalline hydroxyapatite using surfactant template systems: Role of templates in controlling morphology [J]. Mater Sci Eng C, 2009, 29(7): 22942301.
8.	Salarian M, SolatiHashjin M, Shafiei SS, et al. Templatedirected hydrothermal synthesis of dandelionlike hydroxyapatite in the presence of cetyltrimethylammonium bromide and polyethylene glycol [J]. Ceram Int, 2009, 35(7): 25632569.
9.	Li Y, Tjandra W, Tam KC. Synthesis and characterization of nanoporous hydroxyapatite using cationic surfactants as templates [J]. Mater Res Bull, 2008, 43(89): 23182326.
10.	曹献英, 李世普, 张然, 等. 羟基磷灰石纳米粒子对人肝癌细胞增殖及细胞周期的作用研究 [J]. 肿瘤防治杂志, 2003, 10(3): 256258.
11.	Nurse P. A long twentieth century of the cell cycle and beyond [J]. Cell, 2000, 100(1): 7178.
12.	张传海, 许戈良, 葛勇胜, 等. 亚砷酸对肝癌细胞增殖及PCNA, cMyc蛋白表达的影响 [J]. 第四军医大学学报, 2005, 26(14): 13031306.
13.	Suehiro T, Matsumata T, Itasaka H, et al. Clinicopathologic features and prognosis of resected hepatocellular carcinomas of varied sizes with special reference to proliferating cell nuclear antigen [J]. Cancer, 1995, 76(3): 399405.
14.	尹美珍, 李世普, 韩颖超. 羟基磷灰石纳米粒子对肝癌细胞PCNA表达的影响 [J]. 武汉理工大学学报, 2007, 29(8): 5861.
15.	Kannan TP, Nik Ahmad Shah NL, Azlina A, et al. In vivo chromosome aberration test for hydroxyapetite in mice [J]. Med J Malaysia, 2004, 59(Suppl B): 115116.
16.	Itokazu M, Sugiyama T, Ohno T, et al. Development of porous apatite ceramic for local delivery of chemotherapeutic agents [J]. J Biomed Mater Res, 1998, 39(4): 536538.
17.	Benghuzzi H. Longterm sustained delivery of 3′azido2′, 3′dideoxythymidine in vivo by means of HA and TCP delivery devices [J]. Biomed Sci Instrum, 2000, 36: 343348.
18.	齐志涛, 曹献英, 韩颖超, 等. 纳米磷灰石对人肝癌细胞端粒酶基因表达的影响 [J]. 武汉理工大学学报, 2004, 26(7): 4648.
19.	王宁, 李玉, 刘洁. 肝癌患者多药耐药基因检测及其对介入治疗疗效影响分析 [J]. 中国实验诊断学, 2006, 10(6): 572575.
20.	何平, 李金龙, 陈勇, 等. 中晚期肝癌联合介入治疗175例报道 [J]. 中国普外基础与临床杂志, 2010, 17(6): 615617.
21.	Brábek J, Constancio SS, Siesser PF, et al. Crkassociated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRCtransformed cells [J]. Mol Cancer Res, 2005, 3(6): 307315.
22.	潘胜利, 陈孝平, 张万广, 等. Paxillin和p130Cas蛋白在肝癌中的表达及意义 [J]. 中华外科杂志, 2006, 44(23): 16481649.
23.	李高鹏, 陈孝平, 黄志勇, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤Paxillin和P130Cas表达的影响 [J]. 腹部外科, 2008, 21(3): 181183.
24.	王宁, 李玉, 刘洁. 肝癌患者多要耐药基因检测及其对介入治疗疗效影响分析 [J]. 中国实验诊断学, 2006, 10(6): 572575.
25.	Uggla B, Sthl E, Wgster D, et al. BCRP mRNA expression v. clinical outcome in 40 adult AML patients [J]. Leuk Res, 2005, 29(2): 141146.
26.	Li G, Chen X, Wang Q, et al. The role of four multidurg resistance proteins in hepatocellular carcinoma multidrug resistance [J]. J Huazhong Univ Sci Technolog Med Sci, 2007, 27(2): 173175.
27.	叶露, 李高鹏, 宋建新, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤多药耐药相关蛋白表达的影响 [J]. 胃肠病学和肝病学杂志, 2010, 19(5): 437439.
28.	叶义标, 陈涛. 肝癌血管生成与抗血管生成治疗的研究进展 [J]. 中国普外基础与临床杂志, 2009, 16(10): 861865.
29.	徐涛, 陈孝平, 郭永宪, 等. 纳米材料碘油混悬液栓塞对肝肿瘤金属蛋白酶表达的影响 [J]. 中华消化杂志, 2008, 28(5): 335336.
30.	徐涛, 陈孝平, 郭永宪, 等. 纳米材料碘油混悬液栓塞后兔VX2肿瘤组织MT1MMP表达改变的意义 [J]. 中华外科杂志, 2008, 46(8): 606609.
31.	Weidner N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors [J]. Breast Cancer Res Treat, 1995, 36(2): 169180.
32.	孙振纲, 董胜利, 李高鹏, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤生长及血管新生的作用 [J]. 华中科技大学学报（医学版）, 2009, 38(3): 325329.
33.	张艳玲, 梁后杰, 肖文华, 等. 细胞凋亡、PCNA、p53和Fas与肝细胞癌临床病理特征关系的研究 [J]. 第三军医大学学报, 2004, 26(24): 21912193.
34.	罗佳滨, 魏凤香, 孟祥才, 等. 羟基磷灰石纳米粒子诱导肝癌SMMC7721细胞凋亡的研究 [J]. 中国老年学杂志, 2006, 26(1): 7981.
35.	Feng LF, Zhong M, Lei XY, et al. Bcl2 siRNA induced apoptosis and increased sensitivity to 5fluorouracil and HCPT in HepG2 cells [J]. J Drug Target, 2006, 14(1): 2126.
36.	Kanda T, Yokosuka C, Imazeki F, et al. Enhanced sensitivity of human hepatoma cells to 5fluorouracil by small interfering RNA targeting Bcl2 [J]. DNA Cell Biol, 2005, 24(12): 805809.
37.	魏凤香, 张涛, 李红枝, 等. 羟基磷灰石纳米粒子诱导肝癌SMMC7721细胞凋亡后bcl2和bax表达的变化 [J]. 中国老年学杂志, 2008, 28(13): 12611263.

1. Hu J, Liu ZS, Tang SL, et al. Effect of hydroxyapatite nanoparticles on the growth and p53/cMyc protein expression of implanted hepatic VX2 tumor in rabbits by intravenous injection [J]. World J Gastroenterol, 2007, 13(20): 27982802.
2. Baumann S, Fas SC, Giaisi M, et al. Wogonin preferentially kills malignant lymphocytes and suppresses Tcell tumor growth by inducing PLC gamma1 and Ca2+dependent apoptosis [J]. Blood, 2008, 111(4): 23542363.
3. Li G, Dong S, Qu J, et al. Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumor necrosis factoralpha in chemotherapy of multidrug resistant hepatocellular carcinoma [J]. Liver Int, 2010, 30(4): 585592.
4. 关键, 胡道予, 孙振纲, 等. 经动脉灌注纳米微粒治疗兔肝VX2肿瘤的实验研究 [J]. 放射学实践, 2007, 22(8): 786789.
5. Wang A, Yin H, Li D, et al. Effects of organic modifiers on the sizecontrolled synthesis of hydroxyapatite nanorods [J]. Appl Surf Sci, 2007, 253(6): 33113316.
6. Wang A, Yin H, Li D, et al. Sizecontrolled synthesis of hydroxyapatite nanorods in the presence of organic modifiers [J]. Mater Lett, 2007, 61(10): 20842088.
7. Saha SK, Banerjee A, Bancrjee, et al. Synthesis of nanocrystalline hydroxyapatite using surfactant template systems: Role of templates in controlling morphology [J]. Mater Sci Eng C, 2009, 29(7): 22942301.
8. Salarian M, SolatiHashjin M, Shafiei SS, et al. Templatedirected hydrothermal synthesis of dandelionlike hydroxyapatite in the presence of cetyltrimethylammonium bromide and polyethylene glycol [J]. Ceram Int, 2009, 35(7): 25632569.
9. Li Y, Tjandra W, Tam KC. Synthesis and characterization of nanoporous hydroxyapatite using cationic surfactants as templates [J]. Mater Res Bull, 2008, 43(89): 23182326.
10. 曹献英, 李世普, 张然, 等. 羟基磷灰石纳米粒子对人肝癌细胞增殖及细胞周期的作用研究 [J]. 肿瘤防治杂志, 2003, 10(3): 256258.
11. Nurse P. A long twentieth century of the cell cycle and beyond [J]. Cell, 2000, 100(1): 7178.
12. 张传海, 许戈良, 葛勇胜, 等. 亚砷酸对肝癌细胞增殖及PCNA, cMyc蛋白表达的影响 [J]. 第四军医大学学报, 2005, 26(14): 13031306.
13. Suehiro T, Matsumata T, Itasaka H, et al. Clinicopathologic features and prognosis of resected hepatocellular carcinomas of varied sizes with special reference to proliferating cell nuclear antigen [J]. Cancer, 1995, 76(3): 399405.
14. 尹美珍, 李世普, 韩颖超. 羟基磷灰石纳米粒子对肝癌细胞PCNA表达的影响 [J]. 武汉理工大学学报, 2007, 29(8): 5861.
15. Kannan TP, Nik Ahmad Shah NL, Azlina A, et al. In vivo chromosome aberration test for hydroxyapetite in mice [J]. Med J Malaysia, 2004, 59(Suppl B): 115116.
16. Itokazu M, Sugiyama T, Ohno T, et al. Development of porous apatite ceramic for local delivery of chemotherapeutic agents [J]. J Biomed Mater Res, 1998, 39(4): 536538.
17. Benghuzzi H. Longterm sustained delivery of 3′azido2′, 3′dideoxythymidine in vivo by means of HA and TCP delivery devices [J]. Biomed Sci Instrum, 2000, 36: 343348.
18. 齐志涛, 曹献英, 韩颖超, 等. 纳米磷灰石对人肝癌细胞端粒酶基因表达的影响 [J]. 武汉理工大学学报, 2004, 26(7): 4648.
19. 王宁, 李玉, 刘洁. 肝癌患者多药耐药基因检测及其对介入治疗疗效影响分析 [J]. 中国实验诊断学, 2006, 10(6): 572575.
20. 何平, 李金龙, 陈勇, 等. 中晚期肝癌联合介入治疗175例报道 [J]. 中国普外基础与临床杂志, 2010, 17(6): 615617.
21. Brábek J, Constancio SS, Siesser PF, et al. Crkassociated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRCtransformed cells [J]. Mol Cancer Res, 2005, 3(6): 307315.
22. 潘胜利, 陈孝平, 张万广, 等. Paxillin和p130Cas蛋白在肝癌中的表达及意义 [J]. 中华外科杂志, 2006, 44(23): 16481649.
23. 李高鹏, 陈孝平, 黄志勇, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤Paxillin和P130Cas表达的影响 [J]. 腹部外科, 2008, 21(3): 181183.
24. 王宁, 李玉, 刘洁. 肝癌患者多要耐药基因检测及其对介入治疗疗效影响分析 [J]. 中国实验诊断学, 2006, 10(6): 572575.
25. Uggla B, Sthl E, Wgster D, et al. BCRP mRNA expression v. clinical outcome in 40 adult AML patients [J]. Leuk Res, 2005, 29(2): 141146.
26. Li G, Chen X, Wang Q, et al. The role of four multidurg resistance proteins in hepatocellular carcinoma multidrug resistance [J]. J Huazhong Univ Sci Technolog Med Sci, 2007, 27(2): 173175.
27. 叶露, 李高鹏, 宋建新, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤多药耐药相关蛋白表达的影响 [J]. 胃肠病学和肝病学杂志, 2010, 19(5): 437439.
28. 叶义标, 陈涛. 肝癌血管生成与抗血管生成治疗的研究进展 [J]. 中国普外基础与临床杂志, 2009, 16(10): 861865.
29. 徐涛, 陈孝平, 郭永宪, 等. 纳米材料碘油混悬液栓塞对肝肿瘤金属蛋白酶表达的影响 [J]. 中华消化杂志, 2008, 28(5): 335336.
30. 徐涛, 陈孝平, 郭永宪, 等. 纳米材料碘油混悬液栓塞后兔VX2肿瘤组织MT1MMP表达改变的意义 [J]. 中华外科杂志, 2008, 46(8): 606609.
31. Weidner N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors [J]. Breast Cancer Res Treat, 1995, 36(2): 169180.
32. 孙振纲, 董胜利, 李高鹏, 等. 碘油羟基磷灰石纳米粒对兔VX2肝肿瘤生长及血管新生的作用 [J]. 华中科技大学学报（医学版）, 2009, 38(3): 325329.
33. 张艳玲, 梁后杰, 肖文华, 等. 细胞凋亡、PCNA、p53和Fas与肝细胞癌临床病理特征关系的研究 [J]. 第三军医大学学报, 2004, 26(24): 21912193.
34. 罗佳滨, 魏凤香, 孟祥才, 等. 羟基磷灰石纳米粒子诱导肝癌SMMC7721细胞凋亡的研究 [J]. 中国老年学杂志, 2006, 26(1): 7981.
35. Feng LF, Zhong M, Lei XY, et al. Bcl2 siRNA induced apoptosis and increased sensitivity to 5fluorouracil and HCPT in HepG2 cells [J]. J Drug Target, 2006, 14(1): 2126.
36. Kanda T, Yokosuka C, Imazeki F, et al. Enhanced sensitivity of human hepatoma cells to 5fluorouracil by small interfering RNA targeting Bcl2 [J]. DNA Cell Biol, 2005, 24(12): 805809.
37. 魏凤香, 张涛, 李红枝, 等. 羟基磷灰石纳米粒子诱导肝癌SMMC7721细胞凋亡后bcl2和bax表达的变化 [J]. 中国老年学杂志, 2008, 28(13): 12611263.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect and Mechanism of Hydroxyapatite Nanoparticle on Hepatocellular Carcinoma

Abstract Full text Figures/Tables Video References Cited by

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