基于PI3K/AKT/mTOR信号通路探讨中医药通过活性氧介导的内质网应激调控细胞自噬和凋亡抑制结肠癌转移的研究概况
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摘要
肿瘤的发生发展需要微环境的保护与支持,自噬和细胞凋亡在结肠癌的复发转移中起到关键作用。PI3K/AKT/mTOR信号通路是自噬经典信号通路,过度的自噬能够诱导自噬细胞的凋亡,而ROS通过改变细胞的内部环境在细胞凋亡和自噬中发挥重要作用,并且能够通过产生ER应激影响ER中的蛋白错误折叠信号,从而影响细胞生长和死亡。因此,探究基于PI3K/AKT/mTOR信号通路,中医药是否可以通过ROS介导的ER应激调控自噬和细胞凋亡从而抑制结肠癌的转移,为临床提供治疗思路。
The occurrence and development of tumors require the protection and support of microenvironment. Autophagy and apoptosis play a key role in the recurrence and metastasis of colon cancer. PI3K/AKT/mTOR signaling pathway is a classical signaling pathway ofautophagy and excessive autophagy can induce the apoptosis of autophagocytes, while ROS plays an important role in apoptosis and autophagy by changing the internal environment of cells and affect the protein misfolding signal in ER by generating ER stress, affecting cell growth and death. Therefore, based on the PI3K/AKT/mTOR signaling pathway, to explore whether TCM can regulate autophagy and apoptosis through ROS-mediated ER stress to inhibit the metastasis of colon cancer, can provide some clinical treatment ideas.
The occurrence and development of tumors require the protection and support of microenvironment. Autophagy and apoptosis play a key role in the recurrence and metastasis of colon cancer. PI3K/AKT/mTOR signaling pathway is a classical signaling pathway ofautophagy and excessive autophagy can induce the apoptosis of autophagocytes, while ROS plays an important role in apoptosis and autophagy by changing the internal environment of cells and affect the protein misfolding signal in ER by generating ER stress, affecting cell growth and death. Therefore, based on the PI3K/AKT/mTOR signaling pathway, to explore whether TCM can regulate autophagy and apoptosis through ROS-mediated ER stress to inhibit the metastasis of colon cancer, can provide some clinical treatment ideas.
引文
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[5] Canadian Cancer Society. Canadian Cancer Society’s Advisory Committee on Cancer Statistics (2013) Canadian Cancer Statistics. Toronto, 2016.
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[7] Cheng H, Shcherba M, Pendurti G, et al. Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment[J]. Lung Cancer Management,2014,3(1):67.
[8] Yang Y, Cai X, Yang J, et al. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation[J]. Molecular Cancer,2014,13(1):48.
[9] Li HY, Zhang J, Sun LL, et al. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study[J]. Cell Death & Disease, 2015, 6(1):e1604.
[10] Wu M, Lao Y, Xu N, et al. Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death[J]. Phytomedicine International Journal of Phytotherapy & Phytopharmacology, 2015,22(10):902.
[11] Chen M, Guo Y, Zhao R, et al. Ophiopogonin B induces apoptosis, mitotic catastrophe and autophagy in A549 cells[J]. International Journal of Oncology, 2016, 49(1):316-324.
[12] Zhao R, Chen M, Jiang Z, et al. Platycodin-D Induced Autophagy in Non-Small Cell Lung Cancer Cells via PI3K/Akt/mTOR and MAPK Signaling Pathways[J]. J Cancer,2014, 6(7):623-631.
[13] Song S, Tan J, Miao Y, et al.Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress[J].Journal of Cellular Physiology,2017,232(11):2977.
[14] Green D R, Galluzzi L, Kroemer G. Cell biologyMetabolic control of cell death[J]. Science,2014,345(6203):1250256.
[15] Yadav RK, Chae SW, Kim HR, et al. Endoplasmic Reticulum Stress and Cancer[J]. Journal of Cancer Prevention,2014,19(2):75.
[16] Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress[J]. Nature Cell Biology,2011,13(3):184.
[17] Zhou Y, Shu F, Liang X, et al.Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway[J]. Plos One, 2014, 9(2):e89021.
[18] Chang SH, Huang SW, Wang ST, et al. Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells[J].Journal of Dermatological Science,2017:138-148.
[19] Zeeshan, Ali HM, Lee, et al.Endoplasmic Reticulum Stress and Associated ROS[J]. Int J Mol Sci, 2016, 17(3): 327.
[20] Hughes A, Oxford AE, Tawara K, et al. Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis[J]. International Journal of Molecular Sciences,2017,18(3):665.
[21] Galluzzi L, Bravosan Pedro JM, Kroemer G. Organelle-specific initiation of cell death[J]. Nature Cell Biology,2014,16(8):728.
[22] Kaser A. Autophagy and Endoplasmic Reticulum Stress[M]. Springer International Publishing,2017.
[23] San-Miguel B, Crespo I, Sánchez DI, et al. Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis[J].Journal of Pineal Research,2015,59(2):151.
[24] Ouyang G, Xiong L, Liu Z, et al. Inhibition of autophagy potentiates the apoptosis-inducing effects of photodynamic therapy on human colon cancer cells[J]. Photodiagnosis & Photodynamic Therapy,2018.
[25] Jr PJ, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway[J]. Pharmacology & Therapeutics,2014,142(2):164.
[26] Tsai JP, Lee CH, Ying TH, et al. Licochalcone A induces autophagy through PI3K/Akt/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells[J]. Oncotarget, 2015, 6(30):28851.
[27] Sharma K, Le N, Alotaibi M, et al. Cytotoxic autophagy in cancer therapy[J]. International Journal of Molecular Sciences,2014,15(6):10034-10051.
[28] Echeverria I, Liu Y, Gabelli SB, et al. PI3Kα oncogenic mutations weaken the interactions that stabilize the p110α/p85α heterodimer[J]. Febs Journal,2015, 282(18):3528-3542.
[29] Jiang L, Wang C, Lei F, et al. miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway[J]. Oncotarget, 2015, 6(10):8286-8299.
[30] Cuorvo LV, Verderio P, Ciniselli CM, et al. PI3KCA, mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy[J]. Virchows Archiv, 2014,464(1):85-93.
[31] Tanahashi T, Osada S, Yamada A, et al.Extracellular signal-regulated kinase and Akt activation play a critical, role in the process of hepatocyte growth factor-induced epithelial-mesenchymal, transition[J].International Journal of Oncology, 2013, 42(2):556.
[32] Pasquier B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells[J]. Autophagy, 2015, 11(4):725.
[33] Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition[J]. Autophagy, 2014, 10(8):1391-1402.
[34] Wu S, Sun C, Tian D, et al. Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer[J]. International Journal of Clinical & Experimental Pathology,2015,8(4):3882.
[35] Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia[J]. American Journal of Cancer Research,2015,5(4):1281.
[36] Riquelme I, Tapia O, Leal P, et al.miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway[J]. Cellular Oncology,2015,39(1):23-33.
[37] He Z, Deng Y, Li W, et al. Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway[J]. Cell& Bioscience,2014,4(1):2.
[38] Yuge R, Kitadai Y, Shinagawa K, et al. mTOR and PDGF Pathway Blockade Inhibits Liver Metastasis of Colorectal Cancer by Modulating the Tumor Microenvironment[J]. American Journal of Pathology,2015,185(2):399-408.
[39] De AF, Guido C, Santoro M, et al. A novel functional interplay between Progesterone Receptor-B and PTEN, via AKT, modulates autophagy in breast cancer cells[J]. Journal of Cellular & Molecular Medicine,2014,18(11):2252-2265.
[40] MaycotteP, Thorburn A. Autophagy and cancer therapy[J]. Autophagy,2014,85(6):830-838.
[41] Park JM, Chang HJ, Seo M, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14[J].Autophagy, 2016, 12(3):547-564.
[42] Amaravadi RK. Transcriptional regulation of autophagy in RAS-driven cancers[J]. Journal of Clinical Investigation,2015,125(4):1393.
[43] Das TP, Suman S, Alatassi H, et al. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer[J]. Cell Death & Disease, 2016, 7(2):e2111.
[44] 花宝金,朴炳奎.肿瘤虚证及扶正培本治疗的现代免疫机制研究[J].中国中医基础医学杂志,2000,6(3):60-63.
[45] 陈赐慧,花宝金.升降散在肿瘤治疗中的应用体会[J].吉林中医药,2013,33(1):16-18.
[46] Wang Y, Xu R, Xiao J, et al. Quantitative analysis of flavonoids, alkaloids and saponins of Banxia Xiexin decoction using ultra-high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry[J]. JPharm Biomed Anal,2014,88(Complete):525-535.
[47] Qu HH, Qu BP, Liu SC, et al. Mechanism of baicalin compatibility in chinese medicine formula Banxia Xiexin Decoction by pharmacokinetics and indirect competitive enzyme-linked immunosorbent assays in mice[J]. Chinese Journal of Integrative Medicine,2016.
[48] Liang XB, Sun J, Zhao GP. Effect of banxia xiexin decoction on leptin and endothelin-1 of gastric ulcer rat and the optimal combination screening of active components[J].Journal of Chinese Medicinal Materials,2012,35(10):1637.
[49] Chen G, Yang Y, Liu M, et al. Banxia xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice[J]. Journal of Ethnopharmacology, 2015, 166:149-156.
[50] 李凯.辛开苦降法及半夏泻心汤治疗结肠癌的临床和基础研究[D].北京:中国中医科学院,2015.
[51] Gao JL, Lv GY, He BC, et al. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways[J]. Oncology Reports,2013,30(1):292.
[52] Vayghan HJ, Ghadimi SS, Nourazarian AR. Preventive and therapeutic roles of ginseng -focus on colon cancer[J]. Asian Pac J Cancer Prev, 2014, 15(2):585-588.
[53] Wang CZ, Zhang Z, Wan JY, et al. Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer[J]. Nutrients,2015,7(2):799-814.
[54] Wang CZ, Zhang CF, Chen L, et al. Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin[J]. International Journal of Oncology,2015,47(5):1749.
[55] Polier G, Giaisi M, K?hler R, et al. Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263[J]. International Journal of Cancer Journal International Du Cancer,2015,136(3):688-698.
[56] 刘瑞, 花宝金.调理脾胃法防治肿瘤的理论探讨与实践应用[J].中华中医药杂志,2014(4):991-994.
[2] Chow CJ, Alrefaie WB, Abraham A, et al. Does patient rurality predict quality colon cancercare? a population-based study[J]. Diseases of the Colon & Rectum,2015,58(4):415-422.
[3] Li J, Wang Z, Yuan X,et al.The prognostic significance of age in operated and non-operated colorectal cancer[J]. BMC Cancer,2015,15(1):83.
[4] Howlader N, Noone A, Krapcho M, et al. SEER cancer statistics review,1975—2013, National Cancer Institute[EB/OL]. Updated September 12, 2016.
[5] Canadian Cancer Society. Canadian Cancer Society’s Advisory Committee on Cancer Statistics (2013) Canadian Cancer Statistics. Toronto, 2016.
[6] Wei MM, Wang SS, Zheng JL, et al. Herbal compound Teng-Long-Bu-Zhong-Tang inhibits metastasis in human RKO colon carcinoma[J]. Oncology Letters,2017,14(6):7767-7772.
[7] Cheng H, Shcherba M, Pendurti G, et al. Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment[J]. Lung Cancer Management,2014,3(1):67.
[8] Yang Y, Cai X, Yang J, et al. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation[J]. Molecular Cancer,2014,13(1):48.
[9] Li HY, Zhang J, Sun LL, et al. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study[J]. Cell Death & Disease, 2015, 6(1):e1604.
[10] Wu M, Lao Y, Xu N, et al. Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death[J]. Phytomedicine International Journal of Phytotherapy & Phytopharmacology, 2015,22(10):902.
[11] Chen M, Guo Y, Zhao R, et al. Ophiopogonin B induces apoptosis, mitotic catastrophe and autophagy in A549 cells[J]. International Journal of Oncology, 2016, 49(1):316-324.
[12] Zhao R, Chen M, Jiang Z, et al. Platycodin-D Induced Autophagy in Non-Small Cell Lung Cancer Cells via PI3K/Akt/mTOR and MAPK Signaling Pathways[J]. J Cancer,2014, 6(7):623-631.
[13] Song S, Tan J, Miao Y, et al.Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress[J].Journal of Cellular Physiology,2017,232(11):2977.
[14] Green D R, Galluzzi L, Kroemer G. Cell biologyMetabolic control of cell death[J]. Science,2014,345(6203):1250256.
[15] Yadav RK, Chae SW, Kim HR, et al. Endoplasmic Reticulum Stress and Cancer[J]. Journal of Cancer Prevention,2014,19(2):75.
[16] Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress[J]. Nature Cell Biology,2011,13(3):184.
[17] Zhou Y, Shu F, Liang X, et al.Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway[J]. Plos One, 2014, 9(2):e89021.
[18] Chang SH, Huang SW, Wang ST, et al. Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells[J].Journal of Dermatological Science,2017:138-148.
[19] Zeeshan, Ali HM, Lee, et al.Endoplasmic Reticulum Stress and Associated ROS[J]. Int J Mol Sci, 2016, 17(3): 327.
[20] Hughes A, Oxford AE, Tawara K, et al. Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis[J]. International Journal of Molecular Sciences,2017,18(3):665.
[21] Galluzzi L, Bravosan Pedro JM, Kroemer G. Organelle-specific initiation of cell death[J]. Nature Cell Biology,2014,16(8):728.
[22] Kaser A. Autophagy and Endoplasmic Reticulum Stress[M]. Springer International Publishing,2017.
[23] San-Miguel B, Crespo I, Sánchez DI, et al. Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis[J].Journal of Pineal Research,2015,59(2):151.
[24] Ouyang G, Xiong L, Liu Z, et al. Inhibition of autophagy potentiates the apoptosis-inducing effects of photodynamic therapy on human colon cancer cells[J]. Photodiagnosis & Photodynamic Therapy,2018.
[25] Jr PJ, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway[J]. Pharmacology & Therapeutics,2014,142(2):164.
[26] Tsai JP, Lee CH, Ying TH, et al. Licochalcone A induces autophagy through PI3K/Akt/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells[J]. Oncotarget, 2015, 6(30):28851.
[27] Sharma K, Le N, Alotaibi M, et al. Cytotoxic autophagy in cancer therapy[J]. International Journal of Molecular Sciences,2014,15(6):10034-10051.
[28] Echeverria I, Liu Y, Gabelli SB, et al. PI3Kα oncogenic mutations weaken the interactions that stabilize the p110α/p85α heterodimer[J]. Febs Journal,2015, 282(18):3528-3542.
[29] Jiang L, Wang C, Lei F, et al. miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway[J]. Oncotarget, 2015, 6(10):8286-8299.
[30] Cuorvo LV, Verderio P, Ciniselli CM, et al. PI3KCA, mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy[J]. Virchows Archiv, 2014,464(1):85-93.
[31] Tanahashi T, Osada S, Yamada A, et al.Extracellular signal-regulated kinase and Akt activation play a critical, role in the process of hepatocyte growth factor-induced epithelial-mesenchymal, transition[J].International Journal of Oncology, 2013, 42(2):556.
[32] Pasquier B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells[J]. Autophagy, 2015, 11(4):725.
[33] Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition[J]. Autophagy, 2014, 10(8):1391-1402.
[34] Wu S, Sun C, Tian D, et al. Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer[J]. International Journal of Clinical & Experimental Pathology,2015,8(4):3882.
[35] Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia[J]. American Journal of Cancer Research,2015,5(4):1281.
[36] Riquelme I, Tapia O, Leal P, et al.miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway[J]. Cellular Oncology,2015,39(1):23-33.
[37] He Z, Deng Y, Li W, et al. Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway[J]. Cell& Bioscience,2014,4(1):2.
[38] Yuge R, Kitadai Y, Shinagawa K, et al. mTOR and PDGF Pathway Blockade Inhibits Liver Metastasis of Colorectal Cancer by Modulating the Tumor Microenvironment[J]. American Journal of Pathology,2015,185(2):399-408.
[39] De AF, Guido C, Santoro M, et al. A novel functional interplay between Progesterone Receptor-B and PTEN, via AKT, modulates autophagy in breast cancer cells[J]. Journal of Cellular & Molecular Medicine,2014,18(11):2252-2265.
[40] MaycotteP, Thorburn A. Autophagy and cancer therapy[J]. Autophagy,2014,85(6):830-838.
[41] Park JM, Chang HJ, Seo M, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14[J].Autophagy, 2016, 12(3):547-564.
[42] Amaravadi RK. Transcriptional regulation of autophagy in RAS-driven cancers[J]. Journal of Clinical Investigation,2015,125(4):1393.
[43] Das TP, Suman S, Alatassi H, et al. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer[J]. Cell Death & Disease, 2016, 7(2):e2111.
[44] 花宝金,朴炳奎.肿瘤虚证及扶正培本治疗的现代免疫机制研究[J].中国中医基础医学杂志,2000,6(3):60-63.
[45] 陈赐慧,花宝金.升降散在肿瘤治疗中的应用体会[J].吉林中医药,2013,33(1):16-18.
[46] Wang Y, Xu R, Xiao J, et al. Quantitative analysis of flavonoids, alkaloids and saponins of Banxia Xiexin decoction using ultra-high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry[J]. JPharm Biomed Anal,2014,88(Complete):525-535.
[47] Qu HH, Qu BP, Liu SC, et al. Mechanism of baicalin compatibility in chinese medicine formula Banxia Xiexin Decoction by pharmacokinetics and indirect competitive enzyme-linked immunosorbent assays in mice[J]. Chinese Journal of Integrative Medicine,2016.
[48] Liang XB, Sun J, Zhao GP. Effect of banxia xiexin decoction on leptin and endothelin-1 of gastric ulcer rat and the optimal combination screening of active components[J].Journal of Chinese Medicinal Materials,2012,35(10):1637.
[49] Chen G, Yang Y, Liu M, et al. Banxia xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice[J]. Journal of Ethnopharmacology, 2015, 166:149-156.
[50] 李凯.辛开苦降法及半夏泻心汤治疗结肠癌的临床和基础研究[D].北京:中国中医科学院,2015.
[51] Gao JL, Lv GY, He BC, et al. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways[J]. Oncology Reports,2013,30(1):292.
[52] Vayghan HJ, Ghadimi SS, Nourazarian AR. Preventive and therapeutic roles of ginseng -focus on colon cancer[J]. Asian Pac J Cancer Prev, 2014, 15(2):585-588.
[53] Wang CZ, Zhang Z, Wan JY, et al. Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer[J]. Nutrients,2015,7(2):799-814.
[54] Wang CZ, Zhang CF, Chen L, et al. Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin[J]. International Journal of Oncology,2015,47(5):1749.
[55] Polier G, Giaisi M, K?hler R, et al. Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263[J]. International Journal of Cancer Journal International Du Cancer,2015,136(3):688-698.
[56] 刘瑞, 花宝金.调理脾胃法防治肿瘤的理论探讨与实践应用[J].中华中医药杂志,2014(4):991-994.