A Targeting Modality for Destruction of RNA Polymerase I that Possesses Anticancer Activity

Peltonen, Karita; Colis, Laureen; Liu, Hester; Trivedi, Rishi; Moubarek, Michael S.; Moore, Henna M.; Bai, Baoyan; Rudek, Michelle A.; Bieberich, Charles J.; Laiho, Marikki

doi:10.1016/j.ccr.2013.12.009

Cited by 262 publications

(407 citation statements)

References 58 publications

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“…2C) can be highly related to the regulation of gene expression by constituting CpG islands that can be methylated to silence the corresponding gene. The GC-dependent (specific) binding preference of lurbinectedin, to areas surrounding the protein-coding gene promoters, does not exclude the possibility that the drug binds also to other CG-rich sites of the genome targeted by transcription factors, such as SP1 (21,33), or involved in rDNA transcription (34). At any rate, in tumor cells, Pol II is very active and could be arrested by the drug already bound to the DNA.…”

Section: Discussionmentioning

confidence: 99%

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Núñez

Robles

Giraudon

et al. 2016

Molecular Cancer Therapeutics

128

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We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Núñez

Robles

Giraudon

et al. 2016

Molecular Cancer Therapeutics

128

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“…Although BMH-21 intercalates into DNA with high affinity to GC-rich regions, it does not elicit a DNA damage response [127] and its ability to activate p53 is probably mediated by ribosome biogenesis stress. This promising agent was shown to effectively impede the growth of different cancer cells, both in vitro and in vivo [126]. Both cases serve as a proof of concept, demonstrating how specific targeting of RNA PolI can strike tumors at two key points in parallel, suppressing a core cellular function required for the fast proliferation of cancer cells while activating an anti-tumoral p53 response.…”

Section: The Ribosome Biogenesis Machinery As a Putative Cancer Theramentioning

confidence: 99%

“…Strikingly, while CX-5461 induces a very potent p53 response in blood malignancies [125], it can also restrain the growth of human solid tumors independently of p53 [124]. Another small molecule, BMH-21, was recently reported to target PolI activity through its ability to promote the proteasomal degradation of RPA194, the large catalytic subunit of PolI holocomplex [126]. Although BMH-21 intercalates into DNA with high affinity to GC-rich regions, it does not elicit a DNA damage response [127] and its ability to activate p53 is probably mediated by ribosome biogenesis stress.…”

Section: The Ribosome Biogenesis Machinery As a Putative Cancer Theramentioning

confidence: 99%

p53 and ribosome biogenesis stress: The essentials

2014

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a b s t r a c tCell proliferation and cell growth are two tightly linked processes, as the proliferation program cannot be executed without proper accumulation of cell mass, otherwise endangering the fate of the two daughter cells. It is therefore not surprising that ribosome biogenesis, a key element in cell growth, is regulated by many cell cycle regulators. This regulation is exerted transcriptionally and post-transcriptionally, in conjunction with numerous intrinsic and extrinsic signals. Those signals eventually converge at the nucleolus, the cellular compartment that is not only responsible for executing the ribosome biogenesis program, but also serves as a regulatory hub, responsible for integrating and transmitting multiple stress signals to the omnipotent cell fate gatekeeper, p53. In this review we discuss when, how and why p53 is activated upon ribosomal biogenesis stress, and how perturbation of this critical regulatory interplay may impact human disease.

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“…Moreover, the sensitivity was not restricted to MLL-driven AML. To support our findings that the antileukemic effect of CX-5461 is due to on-target inhibition of Pol I transcription, 7 AML cell lines were tested for their sensitivity to 2 additional Pol I inhibitors, BMH-21 14 and low-dose ActD, 15 and an inactive compound (CX-5447), which is structurally similar to CX-5461. 7,16 Both BMH-21 and ActD decreased cell viability after 48 hours in 7 AML cell lines with the level of sensitivity broadly correlating with that of CX-5461 ( Figure 3F).…”

Section: Aml Cells Are Highly Sensitive To Inhibition Of Pol I Transcmentioning

confidence: 99%

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Hein

Cameron

Hannan

et al. 2017

Blood

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Key Points• Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.• CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs. (Blood. 2017;129(21):2882-2895

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A Targeting Modality for Destruction of RNA Polymerase I that Possesses Anticancer Activity

Cited by 262 publications

References 58 publications

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

p53 and ribosome biogenesis stress: The essentials

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

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