• 中国精品科技期刊
  • 中国高校百佳科技期刊
  • 中国中文核心期刊
  • 中国科学引文数据库核心期刊
Advanced Search
SUN Tingzhe. Mathematical modeling of the synergy between hyperthermia and radiotherapy in tumor treatment based on p53 signaling network[J]. Journal of China Pharmaceutical University, 2021, 52(3): 361-370. DOI: 10.11665/j.issn.1000-5048.20210314
Citation: SUN Tingzhe. Mathematical modeling of the synergy between hyperthermia and radiotherapy in tumor treatment based on p53 signaling network[J]. Journal of China Pharmaceutical University, 2021, 52(3): 361-370. DOI: 10.11665/j.issn.1000-5048.20210314

Mathematical modeling of the synergy between hyperthermia and radiotherapy in tumor treatment based on p53 signaling network

Funds: This study was supported by the National Natural Science Foundation of China (No.31971185) and the Key Projects for Outstanding Young Talents in Colleges and Universities of Anhui Province (No.gxyqZD2020031)
More Information
  • Received Date: January 06, 2021
  • Revised Date: May 30, 2021
  • The aim of the current study was to investigate the synergistic effect between temperature and irradiation on p53 dynamics using mathematical model in p53 signaling pathway.Delayed differential equations were used to construct the dynamic p53 model. The accelerated τ-leap stochastic simulation algorithm was used to analyze the stochastic behavior.Loewe and Bliss combination indexes were used to calculate the synergy. Numerical simulations were performed in MATLAB software. Results showed that at relatively lower temperatures, the amplitude and characteristic pitch of p53 pulses varied with changing temperatures.The amplitude and duration of p53 pulses were highly variable. At temperatures below 39 °C, the amplitude of the first p53 pulse was increased when temperature was elevated, whereas the characteristic pitch of p53 pulses was decreased with increasing temperature.Under mild hyperthermia (≥ 41 °C), p53 pulses were disrupted and p53 proteins became steadily accumulated.The patterns of periodicity in auto-correlation plot gradually vanished when the temperature was increased. With the metrics of cumulative and maximal p53 levels, there existed notable synergistic effects between the temperature and irradiation doses. In addition, the effect of temperature on p53 dynamics was reversible.To sum up, temperature could significantly affect dynamic p53 patterns.Radiotherapy may also benefit from hyperthermia in tumor treatment.
  • [1]
    . Proc Natl Acad Sci U S A,1957,43(9):804-811.
    [2]
    Harper CV,Woodcock DJ,Lam C,et al. Temperature regulates NF-κB dynamics and function through timing of A20 transcription[J]. Proc Natl Acad Sci U S A,2018,115(22):E5243-E5249.
    [3]
    Jentsch M,Snyder P,Sheng CB,et al. p53 dynamics in single cells are temperature-sensitive[J]. Sci Rep,2020,10(1):1481.
    [4]
    Batchelor E,Loewer A. Recent progress and open challenges in modeling p53 dynamics in single cells[J]. Curr Opin Syst Biol,2017,3:54-59.
    [5]
    Bieging KT,Mello SS,Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression[J]. Nat Rev Cancer,2014,14(5):359-370.
    [6]
    Wu X,Bayle JH,Olson D,et al. The p53-mdm-2 autoregulatory feedback loop[J]. Genes Dev,1993,7(7a):1126-1132.
    [7]
    Batchelor E,Mock CS,Bhan I,et al. Recurrent initiation:a mechanism for triggering p53 pulses in response to DNA damage[J]. Mol Cell,2008,30(3):277-289.
    [8]
    Marcel V,van Long FN,Diaz JJ. 40 years of research put p53 in translation[J]. Cancers,2018,10(5):152.
    [9]
    Tang QS,Su ZY,Gu W,et al. Mutant p53 on the path to metastasis[J]. Trends Cancer,2020,6(1):62-73.
    [10]
    Gurpinar E,Vousden KH. Hitting cancers'' weak spots:vulnerabilities imposed by p53 mutation[J]. Trends Cell Biol,2015,25(8):486-495.
    [11]
    Sund-Levander M,Forsberg C,Wahren LK. Normal oral,rectal,tympanic and axillary body temperature in adult men and women:a systematic literature review[J]. Scand J Caring Sci,2002,16(2):122-128.
    [12]
    Byrne C,Lim CL. The ingestible telemetric body core temperature sensor:a review of validity and exercise applications[J]. Br J Sports Med,2007,41(3):126-133.
    [13]
    Guilherme L,Kalil J. Rheumatic fever and rheumatic heart disease:cellular mechanisms leading autoimmune reactivity and disease[J]. J Clin Immunol,2010,30(1):17-23.
    [14]
    ó’Fágáin C. Enzyme stabilization—recent experimental progress[J]. Enzym Microb Technol,2003,33(2/3):137-149.
    [15]
    Pelaez F,Manuchehrabadi N,Roy P,et al. Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells[J]. Biomaterials,2018,166:27-37.
    [16]
    Sun TZ,Cui J. A plausible model for bimodal p53 switch in DNA damage response[J]. FEBS Lett,2014,588(5):815-821.
    [17]
    Tanaka T,Halicka HD,Traganos F,et al. Induction of ATM activation,histone H2AX phosphorylation and apoptosis by etoposide:relation to cell cycle phase[J]. Cell Cycle,2007,6(3):371-376.
    [18]
    Hirai Y,Hayashi T,Kubo Y,et al. X-irradiation induces up-regulation of ATM gene expression in wild-type lymphoblastoid cell lines,but not in their heterozygous or homozygous Ataxia-telangiectasia counterparts[J]. Jpn J Cancer Res,2001,92(6):710-717.
    [19]
    Hafner A,Bulyk ML,Jambhekar A,et al. The multiple mechanisms that regulate p53 activity and cell fate[J]. Nat Rev Mol Cell Biol,2019,20(4):199-210.
    [20]
    Walerych D,Olszewski MB,Gutkowska M,et al. Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions[J]. Oncogene,2009,28(48):4284-4294.
    [21]
    Arrhenius S. über die Reaktionsgeschwindigkeit bei der Inversion von Rohrzucker durch S?uren[J]. Z Physik Chem,1889,4:226-248.
    [22]
    Gajjar M,Candeias MM,Malbert-Colas L,et al. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage[J]. Cancer Cell,2012,21(1):25-35.
    [23]
    Chatterjee A,Vlachos DG,Katsoulakis MA. Binomial distribution based tau-leap accelerated stochastic simulation[J]. J Chem Phys,2005,122(2):024112.
    [24]
    Foucquier J,Guedj M. Analysis of drug combinations:current methodological landscape[J]. Pharmacol Res Perspect,2015,3(3):e00149.
    [25]
    Hsing A,Faller DV,Vaziri C. DNA-damaging aryl hydrocarbons induce Mdm2 expression via p53-independent post-transcriptional mechanisms[J]. J Biol Chem,2000,275(34):26024-26031.
    [26]
    Ju J,Schmitz JC,Song B,et al. Regulation of p53 expression in response to 5-fluorouracil in human cancer RKO cells[J]. Clin Cancer Res,2007,13(14):4245-4251.
    [27]
    Mayo LD,Dixon JE,Durden DL,et al. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy[J]. J Biol Chem,2002,277(7):5484-5489.
    [28]
    Rossi M,Demidov ON,Anderson CW,et al. Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites[J]. Nucleic Acids Res,2008,36(22):7168-7180.
    [29]
    Ma L,Wagner J,Rice JJ,et al. A plausible model for the digital response of p53 to DNA damage[J]. Proc Natl Acad Sci U S A,2005,102(40):14266-14271.
    [30]
    Vilenchik MM,Knudson AG. Endogenous DNA double-strand breaks:production,fidelity of repair,and induction of cancer[J]. Proc Natl Acad Sci U S A,2003,100(22):12871-12876.
    [31]
    M?nke G,Cristiano E,Finzel A,et al. Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells[J]. Sci Rep,2017,7:46571.
    [32]
    Harton MD,Koh WS,Bunker AD,et al. p53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions[J]. Mol Syst Biol,2019,15(9):e8685.
    [33]
    Chen X,Chen J,Gan ST,et al. DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control[J]. BMC Biol,2013,11:73.
    [34]
    Yang RZ,Huang B,Zhu YT,et al. Cell type-dependent bimodal p53 activation engenders a dynamic mechanism of chemoresistance[J]. Sci Adv,2018,4(12):eaat5077.
    [35]
    Purvis JE,Karhohs KW,Mock C,et al. p53 dynamics control cell fate[J]. Science,2012,336(6087):1440-1444.
    [36]
    Soares PI,Ferreira IM,Igreja RA,et al. Application of hyperthermia for cancer treatment:recent patents review[J]. Recent Pat Anticancer Drug Discov,2012,7(1):64-73.
    [37]
    Ohnstad HO,Castro R,Sun JC,et al. Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma[J]. Cancer,2013,119(5):1013-1022.
    [38]
    Keizer EM,Bastian B,Smith RW,et al. Extending the linear-noise approximation to biochemical systems influenced by intrinsic noise and slow lognormally distributed extrinsic noise[J]. Phys Rev E,2019,99(5-1):052417.
  • Related Articles

    [1]REN Yanwei, LI Qiyi, HE Bing, LI Haoyu, ZHAO Li, LI Yuyan. Research progress of enzyme-instructed self-assembly molecules for tumor therapy and imaging[J]. Journal of China Pharmaceutical University, 2023, 54(4): 431-442. DOI: 10.11665/j.issn.1000-5048.2023020602
    [2]BAI Yan, GUO Xinyao, QIN Qiliang, YAN Fang. Advances in research on mechanism of lactate dehydrogenase B in tumors[J]. Journal of China Pharmaceutical University, 2023, 54(2): 172-179. DOI: 10.11665/j.issn.1000-5048.20221112001
    [3]XING Xuyang, WANG Xiaochun, HE Wei. Advances in research on tumor immunotherapy and its drug development[J]. Journal of China Pharmaceutical University, 2021, 52(1): 10-19. DOI: 10.11665/j.issn.1000-5048.20210102
    [4]LI Fang, XIN Junbo, SHI Qin, MAO Chengqiong. Advances in near infrared photoimmunotherapy of tumor[J]. Journal of China Pharmaceutical University, 2020, 51(6): 664-674. DOI: 10.11665/j.issn.1000-5048.20200604
    [5]TANG Keqin, LIN Huaqing, LI Shuhong, DONG Lixin, LU Bohong, JIANG Hong. Advances in tumor targeted nanocrystals[J]. Journal of China Pharmaceutical University, 2020, 51(4): 418-424. DOI: 10.11665/j.issn.1000-5048.20200405
    [6]CHEN Ye, YIN Jun, YAO Wenbing, GAO Xiangdong. Advances of DNA-based nanomaterials in tumor therapy[J]. Journal of China Pharmaceutical University, 2020, 51(4): 406-417. DOI: 10.11665/j.issn.1000-5048.20200404
    [7]GAO Qi, HAN Yue, XU Wei, XU Jingjing, WANG Min, ZHANG Juan. Combination of a single-chain variable fragment JZC00 with 2-deoxyglucose inhibited tumor growth in murine models[J]. Journal of China Pharmaceutical University, 2020, 51(2): 206-212. DOI: 10.11665/j.issn.1000-5048.20200212
    [8]WEN Liujing, WANG Chen. Application and research progress of pharmaco-metabonomics in the diagnosis and treatment of tumor[J]. Journal of China Pharmaceutical University, 2015, 46(4): 400-405. DOI: 10.11665/j.issn.1000-5048.20150403
    [9]SUN Zhan-yi, CAI Hui, HUANG Zhi-hua, SHI Lei, CHEN Yong-xiang, LI Yan-mei. Advances of glycopeptide-associated tumor vaccines[J]. Journal of China Pharmaceutical University, 2012, 43(2): 97-106.
    [10]YANG Li, YOU Qi-dong, YANG Yong, GUO Qing-long. Research advances in wogonin′s anti-tumor effects[J]. Journal of China Pharmaceutical University, 2009, 40(6): 576-579.
  • Cited by

    Periodical cited type(6)

    1. 胡渊,傅庆荣. Gadd45β介导热疗促进肾癌细胞凋亡的机制研究. 医药前沿. 2025(17): 1-5 .
    2. 王丹,姜頔,宋越,陆晗笑,刘丽娜. 老年子宫内膜癌组织中miR-30a及p53、S100蛋白表达与临床病理特征、术后复发转移的关系. 中国老年学杂志. 2024(13): 3088-3092 .
    3. 潘熠,林谦,魏兰,张立晶,李蒙. 益气泻肺汤加减方对阿霉素所致心脏毒性干预作用的机制研究. 中西医结合心脑血管病杂志. 2024(21): 3850-3858 .
    4. 侯宇芯,任晋宏,姚红,马慧莱,薛慧清. 基于网络药理学探讨黄芪抗阿霉素心肌细胞毒性的作用机制. 山西大学学报(自然科学版). 2023(03): 708-720 .
    5. 徐茜,寇兰俊,梁晋普,林换森,黄雪菲,吴亚男. 基于网络药理学探讨益气泻肺汤治疗慢性心力衰竭的作用机制. 湖南中医杂志. 2023(08): 150-157 .
    6. 玉苏普瓦吉木·阿力木江,艾孜提艾力·艾海提,木合布力·阿布力孜,杨争,赛力克阿拉·阿里汗,刘正叶. 新型三氟甲基查耳酮类衍生物的设计、合成及体外抗宫颈癌活性. 中国药科大学学报. 2022(06): 674-684 . 本站查看

    Other cited types(0)

Catalog

    Article views (168) PDF downloads (724) Cited by(6)

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return