Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis

被引:451
作者
Drygin, Denis [1 ]
Siddiqui-Jain, Adam [1 ]
O'Brien, Sean [1 ]
Schwaebe, Michael [1 ]
Lin, Amy [1 ]
Bliesath, Josh [1 ]
Ho, Caroline B. [1 ]
Proffitt, Chris [1 ]
Trent, Katy [1 ]
Whitten, Jeffrey P. [1 ]
Lim, John K. C. [1 ]
Von Hoff, Daniel [2 ]
Anderes, Kenna [1 ]
Rice, William G. [1 ]
机构
[1] Cylene Pharmaceut Inc, San Diego, CA 92121 USA
[2] Translat Genom Res Inst, Phoenix, AZ USA
关键词
POLYMERASE-I TRANSCRIPTION; QUADRUPLEX LIGAND RHPS4; CELL-PROLIFERATION; C-MYC; SACCHAROMYCES-CEREVISIAE; COMPLEX-FORMATION; HUMAN GENOME; G4; DNA; CANCER; NUCLEOLIN;
D O I
10.1158/0008-5472.CAN-09-1304
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol 1, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first C-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase 11 clinical trial. [Cancer Res 2009;69(19):7653-61]
引用
收藏
页码:7653 / 7661
页数:9
相关论文
共 57 条
  • [21] Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae
    Hershman, Steve G.
    Chen, Qijun
    Lee, Julia Y.
    Kozak, Marina L.
    Yue, Peng
    Wang, Li-San
    Johnson, F. Brad
    [J]. NUCLEIC ACIDS RESEARCH, 2008, 36 (01) : 144 - 156
  • [22] Hirayoshi K, 1999, METHOD ENZYMOL, V304, P351
  • [23] Guanine nucleotide depletion inhibits pre-ribosornal RNA synthesis and causes nucleolar disruption
    Huang, Min
    Ji, Yanshan
    Itahana, Koji
    Zhang, Yanping
    Mitchell, Beverly
    [J]. LEUKEMIA RESEARCH, 2008, 32 (01) : 131 - 141
  • [24] Prevalence of quadruplexes in the human genome
    Huppert, JL
    Balasubramanian, S
    [J]. NUCLEIC ACIDS RESEARCH, 2005, 33 (09) : 2908 - 2916
  • [25] Drug targeting of the c-MYC promoter to repress gene expression via a G-quadruplex silencer element
    Hurley, Laurence H.
    Von Hoff, Daniel D.
    Siddiqui-Jain, Adam
    Yang, Danzhou
    [J]. SEMINARS IN ONCOLOGY, 2006, 33 (04) : 498 - 512
  • [26] Cisplatin inhibits synthesis of ribosomal RNA in vivo
    Jordan, P
    Carmo-Fonseca, M
    [J]. NUCLEIC ACIDS RESEARCH, 1998, 26 (12) : 2831 - 2836
  • [27] KERSTEN H, 1974, MOL BIOL BIOCH BIOPH, V18, P1
  • [28] Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration
    Leonetti, C
    Amodei, S
    D'Angelo, C
    Rizzo, A
    Benassi, B
    Antonelli, A
    Elli, R
    Stevens, MFG
    D'Incalci, M
    Zupi, G
    Biroccio, A
    [J]. MOLECULAR PHARMACOLOGY, 2004, 66 (05) : 1138 - 1146
  • [29] LIM JK, 2009, 100 AACR ANN M 2009, P868
  • [30] CK2-mediated stimulation of Pol I transcription by stabilization of UBF-SL1 interaction
    Lin, Chih-Yin
    Navarro, Sonia
    Reddy, Sita
    Comai, Lucio
    [J]. NUCLEIC ACIDS RESEARCH, 2006, 34 (17) : 4752 - 4766