The role of p53 in cancer drug resistance and targeted chemotherapy

被引:415
|
作者
Hientz, Karin [1 ]
Mohr, Andre [1 ]
Bhakta-Guha, Dipita [2 ]
Efferth, Thomas [1 ]
机构
[1] Johannes Gutenberg Univ Mainz, Inst Pharm & Biochem, Dept Pharmaceut Biol, Mainz, Germany
[2] SASTRA Univ, Sch Chem & Bio Technol, Thanjavur, Tamil Nadu, India
关键词
cytotoxic chemotherapy; drug resistance; medicinal chemistry; prognostic factors; targeted chemotherapy; PROTEIN-PROTEIN INTERACTION; SMALL-MOLECULE ANTAGONISTS; TUMOR-SUPPRESSOR PATHWAY; STRUCTURE-BASED DESIGN; DNA MISMATCH REPAIR; MUTANT P53; WILD-TYPE; P53-MDM2; INTERACTION; ACTIVATES P53; BREAST-CANCER;
D O I
10.18632/oncotarget.13475
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53's regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.
引用
收藏
页码:8921 / 8946
页数:26
相关论文
共 50 条
  • [1] Role of p53 in drug resistance in ovarian cancer
    Shelling, AN
    LANCET, 1997, 349 (9054): : 744 - 745
  • [2] p53 in drug resistance in ovarian cancer
    Lavarino, C
    Delia, D
    DiPalma, S
    Zunino, F
    Pilotti, S
    LANCET, 1997, 349 (9064): : 1556 - 1556
  • [3] Investigation of the role of p53 in chemotherapy resistance of lung cancer cell lines
    Breen, Laura
    Heenan, Mary
    Amberger-Murphy, Verena
    Clynes, Martin
    ANTICANCER RESEARCH, 2007, 27 (3A) : 1361 - 1364
  • [4] Role of p53 in breast cancer progression: An insight into p53 targeted therapy
    Marvalim, Charlie
    Datta, Arpita
    Lee, Soo Chin
    THERANOSTICS, 2023, 13 (04): : 1421 - 1442
  • [5] Predicting response to cancer chemotherapy: the role of p53
    Weller, M
    CELL AND TISSUE RESEARCH, 1998, 292 (03) : 435 - 445
  • [6] Predicting response to cancer chemotherapy: the role of p53
    Michael Weller
    Cell and Tissue Research, 1998, 292 : 435 - 445
  • [7] P53, BCL-2 and drug resistance in cancer
    Therwath, A
    MULTI-DRUG RESISTANCE IN EMERGING AND RE-EMERGING DISEASES, 2000, : 249 - 252
  • [8] Role of p53 in determining response of breast cancer cells to chemotherapy
    Hinnis, A
    Luckett, J
    Walker, RA
    JOURNAL OF PATHOLOGY, 2003, 201 : 27A - 27A
  • [9] Hepatocellular Carcinoma and Chemotherapy: The Role of p53
    Brito, A. F.
    Abrantes, A. M.
    Pinto-Costa, C.
    Gomes, A. R.
    Mamede, A. C.
    Casalta-Lopes, J.
    Goncalves, A. C.
    Sarmento-Ribeiro, A. B.
    Tralhao, J. G.
    Botelho, M. F.
    CHEMOTHERAPY, 2012, 58 (05) : 381 - 386
  • [10] p53 Family in Resistance to Targeted Therapy of Melanoma
    Vlasic, Ignacija
    Horvat, Andela
    Tadijan, Ana
    Slade, Neda
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (01)