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Mechanism of the effect of arginine on radiosensitization of metastatic brain tumors
Liu Xueping1, Jiang Yu2, Wang Ruisi1, Li Xiaochun1, Tan Bangxian1
1Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; 2Department of Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
Abstract Brain metastases are the most common intracranial malignancies, and radiotherapy is an effective treatment of controlling the localized lesions. However, conventional radiotherapy techniques have their own shortcomings that limit the effectiveness of radiotherapy. Metastatic brain tumors are highly likely to recur or progress after treatment. Clinical studies have shown that arginine can penetrate the blood-brain barrier and subsequently improve the radiosensitization of metastatic brain tumors. In this article, the mechanisms underlying the effect of arginine on the radiosensitization of metastatic brain tumors by inhibition of tumor glycolytic metabolism, reduction of DNA damage repair and alteration of tumor hemodynamic parameters were reviewed, aiming to provide new ideas for clinical research and treatment of brain metastases.
Corresponding Authors:
Tan Bangxian,Email: tbx_nsmc@126.com
Cite this article:
Liu Xueping,Jiang Yu,Wang Ruisi et al. Mechanism of the effect of arginine on radiosensitization of metastatic brain tumors[J]. Chinese Journal of Radiation Oncology, 2023, 32(7): 657-662.
Liu Xueping,Jiang Yu,Wang Ruisi et al. Mechanism of the effect of arginine on radiosensitization of metastatic brain tumors[J]. Chinese Journal of Radiation Oncology, 2023, 32(7): 657-662.
[1] Brastianos HC, Cahill DP, Brastianos PK.Systemic therapy of brain metastases[J]. Curr Neurol Neurosci Rep, 2015,15(2):518. DOI: 10.1007/s11910-014-0518-9. [2] 中国医师协会肿瘤医师分会, 中国医疗保健国际交流促进会肿瘤内科分会. 肺癌脑转移中国治疗指南(2021年版)[J]. 中华肿瘤杂志, 2021,43(3):269-281. DOI: 10.3760/cma.j.cn112152-20210104-00009. Chinese Association for Clinical Oncologists, Medical Oncology Branch of Chinese International Exchange and Promotion Association for Medical and Healthcare. Clinical practice guideline for brain metastases of lung cancer in China (2021 version)[J]. Chin J Oncol, 2021,43(3):269-281. DOI: 10.3760/cma.j.cn112152-20210104-00009. [3] Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology[J]. J Neurooncol, 2005,75(1):5-14. DOI: 10.1007/s11060-004-8093-6. [4] Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization[J]. Nat Rev Cancer, 2009,9(4):274-284. DOI: 10.1038/nrc2622. [5] Chiarion-Sileni V, Murr R, Pigozzo J, et al. Brain metastases from malignant melanoma[J]. Forum (Genova), 2003, 13(2):170-182. [6] Fidler IJ. The biology of brain metastasis: challenges for therapy[J]. Cancer J, 2015,21(4):284-293. DOI: 10.1097/PPO.0000000000000126. [7] Soffietti R, Abacioglu U, Baumert B, et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)[J]. Neuro Oncol, 2017,19(2):162-174. DOI: 10.1093/neuonc/now241. [8] Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline[J]. J Clin Oncol, 2022,40(5):492-516. DOI: 10.1200/JCO.21.02314. [9] Kim BM, Hong Y, Lee S, et al. Therapeutic implications for overcoming radiation resistance in cancer therapy[J]. Int J Mol Sci, 2015,16(11):26880-26913. DOI: 10.3390/ijms161125991. [10] Chao ST, Barnett GH, Vogelbaum MA, et al. Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy[J]. Cancer, 2008,113(8):2198-2204. DOI: 10.1002/cncr.23821. [11] Mulvenna P, Nankivell M, Barton R, et al.Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial[J]. Lancet, 2016,388(10055):2004-2014. DOI: 10.1016/S0140-6736(16)30825-X. [12] Babaye Abdollahi B, Malekzadeh R, Pournaghi Azar F, et al. Main approaches to enhance radiosensitization in cancer cells by nanoparticles: a systematic review[J]. Adv Pharm Bull, 2021,11(2):212-223. DOI: 10.34172/apb. 2021.025. [13] Rathi S, Griffith JI, Zhang W, et al. The influence of the blood-brain barrier in the treatment of brain tumours[J]. J Intern Med, 2022,292(1):3-30. DOI: 10.1111/joim.13440. [14] Koga Y, Povalko N, Inoue E, et al. Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research[J]. J Neurol, 2018,265(12):2861-2874. DOI: 10.1007/s00415-018-9057-7. [15] Buijs N, van Bokhorst-de van der Schueren MA, Langius JA, et al. Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival[J]. Am J Clin Nutr, 2010,92(5):1151-1156. DOI: 10.3945/ajcn.2010.29532. [16] Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity[J]. Cell, 2016,167(3):829-842.e13. DOI: 10.1016/j.cell.2016.09.031. [17] Wang YJ, Ma QY, Gao XP, et al. Effect of arginine on the expressions of proliferating cell nuclear antigen and survivin in colorectal tumor[J]. Chin J Clin Nutr, 2006:378-381. [18] Braga M, Gianotti L, Vignali A, et al. Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer[J]. Surgery, 2002,132(5):805-814. DOI: 10.1067/msy.2002.128350. [19] Marullo R, Castro M, Yomtoubian S, et al. The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases[J]. Sci Adv, 2021,7(45):eabg1964. DOI: 10.1126/sciadv.abg1964. [20] Wu GY, Bazer FW, Davis TA, et al. Arginine metabolism and nutrition in growth, health and disease[J]. Amino Acids, 2009,37(1):153-168. DOI: 10.1007/s00726-008-0210-y. [21] Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression[J]. Nat Rev Cancer, 2006,6(7):521-534. DOI: 10.1038/nrc1910. [22] 惠均武, 高小鹏, 马清涌, 等. L-精氨酸对大肠肿瘤细胞中Ki67、iNOS的表达及血清NO浓度的影响[J].陕西医学杂志,2011,40(6):666-667,673. DOI: 10.3969/j.issn.1000-7377.2011.06.009. Hui JW, Gao XP, Ma QY, et al. The effects of L-arginine on the cell proliferation in patients with colorectal tumor and its mechanisms[J].Shanxi Medical Journal,2011,40(6):666-667,673. DOI: 10.3969/j.issn.1000-7377.2011. 06.009. [23] Channon KM, Guzik TJ. Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors[J]. J Physiol Pharmacol, 2002, 53(4 Pt 1):515-524. [24] Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease[J]. Physiol Rev, 2007,87(1):315-424. DOI: 10.1152/physrev.00029.2006. [25] White MR, Garcin ED. D-glyceraldehyde-3-phosphate dehydrogenase structure and function[J]. Subcell Biochem, 2017,83:413-453. DOI: 10.1007/978-3-319-46503-6_15. [26] Pacher P, Szabo C. Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease[J]. Am J Pathol, 2008,173(1):2-13. DOI: 10.2353/ajpath.2008. 080019. [27] Warburg O. The metabolism of carcinoma cells[J]. J Cancer Res, 1925, 9(1):148-163. DOI: 10.1158/jcr. 1925.148. [28] Kim SY. Cancer energy metabolism: shutting power off cancer factory[J]. Biomol Ther (Seoul), 2018,26(1):39-44. DOI: 10.4062/biomolther.2017.184. [29] San-Millán I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect[J]. Carcinogenesis, 2017,38(2):119-133. DOI: 10.1093/carcin/bgw127. [30] Yu L, Chen X, Sun XQ, et al. The glycolytic switch in tumors: how many players are involved?[J]. J Cancer, 2017,8(17):3430-3440. DOI: 10.7150/jca.21125. [31] Dhup S, Dadhich RK, Porporato PE, et al. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis[J]. Curr Pharm Des, 2012,18(10):1319-1330. DOI: 10.2174/138161212799504902. [32] Certo M, Tsai CH, Pucino V, et al. Lactate modulation of immune responses in inflammatory versus tumour microenvironments[J]. Nat Rev Immunol, 2021,21(3):151-161. DOI: 10.1038/s41577-020-0406-2. [33] de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, et al. Lactate in the regulation of tumor microenvironment and therapeutic approaches[J]. Front Oncol, 2019,9:1143. DOI: 10.3389/fonc.2019.01143. [34] Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer[J]. Cancer Res, 2011,71(22):6921-6925. DOI: 10.1158/0008-5472.CAN-11-1457. [35] Mayer A, Vaupel P. Hypoxia, lactate accumulation,acidosis: siblings or accomplices driving tumor progression and resistance to therapy?[J]. Adv Exp Med Biol, 2013,789:203-209. DOI: 10.1007/978-1-4614-7411-1_28. [36] Liu KX, Everdell E, Pal S, et al.Harnessing lactate metabolism for radiosensitization[J]. Front Oncol, 2021,11:672339. DOI: 10.3389/fonc.2021.672339. [37] Sattler UG, Meyer SS, Quennet V, et al. Glycolytic metabolism and tumour response to fractionated irradiation[J]. Radiother Oncol, 2010,94(1):102-109. DOI: 10.1016/j.radonc.2009.11.007. [38] Koukourakis M, Tsolou A, Pouliliou S, et al. Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide[J]. Biochem Biophys Res Commun, 2017,491(4):932-938. DOI: 10.1016/j.bbrc.2017.07.138. [39] Bola BM, Chadwick AL, Michopoulos F, et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport[J]. Mol Cancer Ther, 2014,13(12):2805-2816. DOI: 10.1158/1535-7163.MCT-13-1091. [40] Arroyo-Crespo JJ, Armiñán A, Charbonnier D, et al. Characterization of triple-negative breast cancer preclinical models provides functional evidence of metastatic progression[J]. Int J Cancer, 2019,145(8):2267-2281. DOI: 10.1002/ijc.32270. [41] Pastwa E, Neumann RD, Mezhevaya K, et al. Repair of radiation-induced DNA double-strand breaks is dependent upon radiation quality and the structural complexity of double-strand breaks[J]. Radiat Res, 2003,159(2):251-261. DOI: 10.1667/0033-7587(2003)159 [0251:roridd]2.0.co;2. [42] Li Y, Li H, Peng W, et al. DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair[J]. Mol Med Rep, 2015,12(1):1328-1334. DOI: 10.3892/mmr.2015.3505. [43] Morikawa E, Rosenblatt S, Moskowitz MA. L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia[J]. Br J Pharmacol, 1992,107(4):905-907. DOI: 10.1111/j.1476-5381.1992.tb13382.x. [44] Sun D, Messina EJ, Koller A, et al. Endothelium-dependent dilation to L-arginine in isolated rat skeletal muscle arterioles[J]. Am J Physiol, 1992,262(4 Pt 2):H1211-1216. DOI: 10.1152/ajpheart.1992.262.4.H1211. [45] Bode-Böger SM, Böger RH, Creutzig A, et al. L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects[J]. Clin Sci (Lond), 1994,87(3):303-310. DOI: 10.1042/cs087 0303. [46] Fukumura D, Yuan F, Endo M, et al. Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability,leukocyte-endothelial interactions[J]. Am J Pathol, 1997, 150(2):713-725. [47] Zhu XH, Du JX, Zhu D, et al.Recent research on methods to improve tumor hypoxia environment[J]. Oxid Med Cell Longev, 2020,2020:5721258. DOI: 10.1155/2020/5721258. [48] Tu JY, Tu K, Xu HR, et al. Improving tumor hypoxia and radiotherapy resistance via in situ nitric oxide release strategy[J]. Eur J Pharm Biopharm, 2020,150:96-107. DOI: 10.1016/j.ejpb.2020.03.003. [49] Sonveaux P, Dessy C, Brouet A, et al.Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery[J]. FASEB J, 2002,16(14):1979-1981. DOI: 10.1096/fj.02-0487fje. [50] Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity[J]. Cell, 2016,167(3):829-842.e13. DOI: 10.1016/j.cell.2016.09.031. [51] Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments[J]. Cancer Cell, 2022,40(2):201-218.e9. DOI: 10.1016/j.ccell.2022.01.001. [52] Watson MJ, Vignali P, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid[J]. Nature, 2021,591(7851):645-651. DOI: 10.1038/s41586-020-03045-2. [53] Shukla J, Chatterjee S, Thakur VS, et al. L-arginine reverses radiation-induced immune dysfunction: the need for optimum treatment window[J]. Radiat Res, 2009,171(2):180-187. DOI: 10.1667/RR1241.1. [54] Wardman P, Rothkamm K, Folkes LK, et al. Radiosensitization by nitric oxide at low radiation doses[J]. Radiat Res, 2007,167(4):475-484. DOI: 10.1667/RR0827.1. [55] Wilson A, Menon V, Khan Z, et al.Nitric oxide-donor/PARP-inhibitor combination: a new approach for sensitization to ionizing radiation[J]. Redox Biol, 2019,24:101169. DOI: 10.1016/j.redox.2019.101169. [56] Mustafa AG, Al-Shboul O, Alfaqih MA, et al. Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins[J]. Arch Physiol Biochem, 2018,124(5):418-423. DOI: 10.1080/13813455.2017. 1415939. [57] Therond P. [Oxidative stress and damages to biomolecules (lipids, proteins, DNA)][J]. Ann Pharm Fr, 2006,64(6):383-389. DOI: 10.1016/s0003-4509(06)75333-0. [58] Goodman JE, Hofseth LJ, Hussain SP, et al. Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease[J]. Environ Mol Mutagen, 2004,44(1):3-9. DOI: 10.1002/em.20024. [59] Takahashi A, Matsumoto H, Ohnishi T. Hdm2 and nitric oxide radicals contribute to the p53-dependent radioadaptive response[J]. Int J Radiat Oncol Biol Phys, 2008,71(2):550-558. DOI: 10.1016/j.ijrobp.2008. 02.001. [60] Tang CH, Wei W, Liu L. Regulation of DNA repair by S-nitrosylation[J]. Biochim Biophys Acta, 2012,1820(6):730-735. DOI: 10.1016/j.bbagen.2011.04.014. [61] Nickoloff JA, Sharma N, Taylor L.Clustered DNA double-strand breaks: biological effects and relevance to cancer radiotherapy[J]. Genes (Basel), 2020,11(1) :99. DOI: 10.3390/genes11010099. [62] Folkes LK, O'Neill P. Modification of DNA damage mechanisms by nitric oxide during ionizing radiation[J]. Free Radic Biol Med, 2013,58:14-25. DOI: 10.1016/j.freeradbiomed.2013.01.014.
2023, Vol. 32 
