细胞衰老与卵巢癌铂类化疗敏感性关系的研究进展

doi:10.3969/j.issn.1004-616x.2025.04.005

摘要/Abstract

摘要： 以铂类药物为基础的化疗是卵巢癌的标准治疗方法之一。然而，铂类化疗耐药已成为制约进一步改善卵巢癌患者预后的瓶颈。在DNA损伤或其他应激因素的触发下，部分细胞可进入一种稳定的细胞周期停滞状态，称为细胞衰老。近年来的研究表明，细胞衰老在铂类耐药中扮演双重角色，既可能增强治疗敏感性，也可能促成耐药性，二者之间的关系较为复杂。许多靶向细胞衰老相关通路以改善化疗敏感性的新型药物正在研究中。本文对细胞衰老与卵巢癌铂类化疗耐药之间的关系及其作为治疗靶点的潜在价值进行了梳理和综述。

关键词: 细胞衰老, 卵巢癌, 铂耐药, 化疗, 衰老相关分泌表型

中图分类号:

R737.31

李俊毅, 肖汀. 细胞衰老与卵巢癌铂类化疗敏感性关系的研究进展[J]. 癌变·畸变·突变, 2025, 37(4): 277-280.

LI Junyi, XIAO Ting. Research progress on the relationship between cell senescence and sensitivity to platinum-based chemotherapy in ovarian cancer[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2025, 37(4): 277-280.

参考文献

[1] HAN B F, ZHENG R S, ZENG H M, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1): 47-53.
[2] RICHARDSON D L, ESKANDER R N, O’MALLEY D M. Advances in ovarian cancer care and unmet treatment needs for patients with platinum resistance: a narrative review[J]. JAMA Oncol, 2023, 9(6): 851-859.
[3] WANG L, WANG X, ZHU X P, et al. Drug resistance in ovarian cancer: from mechanism to clinical trial[J]. Mol Cancer, 2024, 23(1): 66.
[4] HUANG W J, HICKSON L J, EIRIN A, et al. Cellular senescence: the good, the bad and the unknown[J]. Nat Rev Nephrol, 2022, 18(10): 611-627.
[5] WANG B S, HAN J, ELISSEEFF J H, et al. The senescence-associated secretory phenotype and its physiological and pathological implications[J]. Nat Rev Mol Cell Biol, 2024, 25(12): 958-978.
[6] SALEH T, BLOUKH S, HASAN M, et al. Therapy-induced senescence as a component of tumor biology: Evidence from clinical cancer[J]. Biochim Biophys Acta Rev Cancer, 2023, 1878(6): 188994.
[7] WANG Z H, LIU H O, XU C J. Cellular senescence in the treatment of ovarian cancer[J]. Int J Gynecol Cancer, 2018, 28(5): 895-902.
[8] VEENSTRA J P, BITTENCOURT L F F, AIRD K M. The senescence-associated secretory phenotype in ovarian cancer dissemination[J]. Am J Physiol Cell Physiol, 2022, 323(1): C125-C132.
[9] WANG L, XIONG B, LU W, et al. Senolytic drugs dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer[J]. Biomed Pharmacother, 2024, 174: 116474.
[10] 李伟. 顺铂诱导肿瘤细胞衰老相关新基因的筛选及功能鉴定[D]. 武汉: 华中科技大学, 2009.
[11] MEJIA PE-A C, SKIPPER T A, HSU J, et al. Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations[J]. Sci Rep, 2023, 13(1): 19232.
[12] SCHMITT C A, WANG B S, DEMARIA M. Senescence and cancer - role and therapeutic opportunities[J]. Nat Rev Clin Oncol, 2022, 19(10): 619-636.
[13] SCHMITT C A, FRIDMAN J S, YANG M, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy[J]. Cell, 2002, 109(3): 335-346.
[14] PAFFENHOLZ S V, SALVAGNO C, HO Y J, et al. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer[J]. Proc Natl Acad Sci USA, 2022, 119(5): e2117754119.
[15] SUN H Z, WANG H S, WANG X, et al. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells[J]. Theranostics, 2020, 10(15): 6928-6945.
[16] NAKAYAMA K, RAHMAN M, RAHMAN M T, et al. Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer[J]. Oncol Lett, 2017, 13(6): 4713-4719.
[17] D’ANTONA L, DATTILO V, CATALOGNA G, et al. In preclinical model of ovarian cancer, the SGK1 inhibitor SI113 counteracts the development of paclitaxel resistance and restores drug sensitivity[J]. Transl Oncol, 2019, 12(8): 1045-1055.
[18] 周丹. miR-429/ZEB1轴调控铂类耐药卵巢癌细胞敏感性的机制研究[D]. 南宁: 广西医科大学, 2021.
[19] SUN Y, JIN L, LIU J H, et al. Interfering EZH2 expression reverses the cisplatin resistance in human ovarian cancer by inhibiting autophagy[J]. Cancer Biother Radiopharm, 2016, 31(7): 246-252.
[20] DEMARIA M, O’LEARY M N, CHANG J H, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse[J]. Cancer Discov, 2017, 7(2): 165-176.
[21] SANTANA-RIVERA Y, RABELO-FERNáNDEZ R J, QUI-ONES-DíAZ B I, et al. Erratum: Reduced expression of enolase-1 correlates with high intracellular glucose levels and increased senescence in cisplatin-resistant ovarian cancer cells[J]. Am J Transl Res, 2021, 13(11): 13219.
[22] ÖZEŞ A R, MILLER D F, ÖZEŞ O N, et al. NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer[J]. Oncogene, 2016, 35(41): 5350-5361.
[23] WU H, SUN C G, CAO W Y, et al. Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer[J]. Cancer Lett, 2024, 602: 217192.
[24] WEINER-GORZEL K, DEMPSEY E, MILEWSKA M, et al. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells[J]. Cancer Med, 2015, 4(5): 745-758.
[25] RABELO-FERNáNDEZ R J, SANTIAGO-SáNCHEZ G S, SHARMA R K, et al. Reduced RBPMS levels promote cell proliferation and decrease cisplatin sensitivity in ovarian cancer cells[J]. Int J Mol Sci, 2022, 23(1): 535.
[26] MILANOVIC M, FAN D N Y, BELENKI D, et al. Senescence-associated reprogramming promotes cancer stemness[J]. Nature, 2018, 553(7686): 96-100.
[27] XIONG J, FU Y Y, HUANG J Z, et al. Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer[J]. Front Endocrinol (Lausanne), 2023, 14: 1265525.
[28] YE X, WEINBERG R A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression[J]. Trends Cell Biol, 2015, 25(11): 675-686.
[29] VICTORELLI S, SALMONOWICZ H, CHAPMAN J, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP[J]. Nature, 2023, 622(7983): 627-636.
[30] NACARELLI T, FUKUMOTO T, ZUNDELL J A, et al. NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer[J]. Cancer Res, 2020, 80(4): 890-900.
[31] WANG Y N, ZONG X Y, MITRA S, et al. IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells[J]. JCI Insight, 2018, 3(23): e122360.
[32] NIU N, YAO J, BAST R C, et al. IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming[J]. Oncogenesis, 2021, 10(9): 65.
[33] SHEN C C, KANG Y H, ZHAO M, et al. WNT16B from ovarian fibroblasts induces differentiation of regulatory T cells through β-catenin signal in dendritic cells[J]. Int J Mol Sci, 2014, 15(7): 12928-12939.
[34] áLVAREZ-ABRIL B, GARCíA-MARTíNEZ E, GALLUZZI L. Platinum-based chemotherapy inflames the ovarian carcinoma microenvironment through cellular senescence[J]. Oncoimmunology, 2022, 11(1): 2052411.
[35] THAPA B V, BANERJEE M, GLIMM T, et al. The senescent mesothelial matrix accentuates colonization by ovarian cancer cells[J]. Cell Mol Life Sci, 2023, 81(1): 2.
[36] MIKU-A-PIETRASIK J, URUSKI P, SOSI-SKA P, et al. Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases[J]. Cell Death Dis, 2016, 7(12): e2565.
[37] RUHLAND M K, LOZA A J, CAPIETTO A H, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis[J]. Nat Commun, 2016, 7: 11762.
[38] FLEURY H, MALAQUIN N, TU V, et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence[J]. Nat Commun, 2019, 10: 2556.
[39] 彭碧. EIF4G1在卵巢癌中的表达及对卵巢癌细胞增殖和自噬的影响[D]. 长沙: 中南大学, 2023.
[40] XIONG J Q, DONG L, LV Q Y, et al. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes[J]. Clin Transl Med, 2024, 14(9): e1772.
[41] PUJADE-LAURAINE E, HILPERT F, WEBER B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial[J]. J Clin Oncol, 2014, 32(13): 1302-1308.
[42] MURALIKRISHNAN V, FANG F, GIVEN T C, et al. A novel ALDH1A1 inhibitor blocks platinum-induced senescence and stemness in ovarian cancer[J]. Cancers (Basel), 2022, 14(14): 3437.
[43] ZHANG X D, YAO J, LI X R, et al. Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer[J]. Sci Adv, 2023, 9(29): eadf7195.
[44] CHEN W J, ZHUANG X J, CHEN Y Y, et al. Discovery of potent and selective CDK2 inhibitors with high safety and favorable bioavailability for the treatment of cancer[J]. Eur J Med Chem, 2025, 290: 117503.
[45] 柯小平, 李莉, 李经维, 等. PTEN通过靶向P21诱导卵巢癌细胞衰老的机制研究[J]. 中国免疫学杂志, 2021, 37(12): 1461-1467.