Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age

Ferreira, Rita; Schneekloth, John S.; Panov, Kostya I.; Hannan, Katherine M.

doi:10.3390/cells9020266

Cited by 141 publications

(131 citation statements)

References 121 publications

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“…Besides, Top1 inhibitors are nonspecific RNA polymerase inhibitors. An RNA Pol1-mediated ribosomal RNA gene increase is involved in cancer progression, through the control of cellular checkpoints and chromatin structure and is, therefore, an interesting co-target [ 206 ]. CuC dual Top inhibitors display a high antiproliferative activity.…”

Section: Future Strategies For Copper Complexes As Top Inhibitors mentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

131

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Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

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Section: Future Strategies For Copper Complexes As Top Inhibitors mentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

131

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“…The control of rRNA transcription is a major factor determining the amount of ribosome production [ 3 ], and thus, the levels of rRNA transcription affect multiple cellular activities including cell proliferation [ 4 , 5 ]. It was reported over a century ago that the number and sizes of nucleoli, the sites of ribosome biogenesis, are increased in cancer cells, and inhibition of rRNA transcription has been proposed as a therapeutic strategy against cancer cells [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription

Tanaka

Obinata

Konishi

et al. 2020

Cells

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Metformin, which is suggested to have anti-cancer effects, activates KDM2A to reduce rRNA transcription and proliferation of cancer cells. Thus, the specific activation of KDM2A may be applicable to the treatment of cancers. In this study, we screened a food-additive compound library to identify compounds that control cell proliferation. We found that gallic acid activated KDM2A to reduce rRNA transcription and cell proliferation in breast cancer MCF-7 cells. Gallic acid accelerated ROS production and activated AMPK. When ROS production or AMPK activity was inhibited, gallic acid did not activate KDM2A. These results suggest that both ROS production and AMPK activation are required for activation of KDM2A by gallic acid. Gallic acid did not reduce the succinate level, which was required for KDM2A activation by metformin. Metformin did not elevate ROS production. These results suggest that the activation of KDM2A by gallic acid includes mechanisms distinct from those by metformin. Therefore, signals from multiple intracellular conditions converge in KDM2A to control rRNA transcription. Gallic acid did not induce KDM2A-dependent anti-proliferation activity in non-tumorigenic MCF10A cells. These results suggest that the mechanism of KDM2A activation by gallic acid may be applicable to the treatment of breast cancers.

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“…Due to the promising results of this preclinical data, CX-5461 is currently tested in several clinical trials. A phase I clinical trial has successfully been completed in patients with hematological cancers and at present phase I/II trails are undergoing for solid tumors, including metastatic breast cancer, ovarian, and pancreas cancer [169]. Thus, selectively targeting ribosome biogenesis could provide a novel and efficient strategy in cancer therapy.…”

Section: Implications For Cancer Biologymentioning

confidence: 99%

The Nucleolus and PARP1 in Cancer Biology

Engbrecht¹,

Mangerich²

2020

Cancers

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The nucleolus has been known for a long time to fulfill crucial functions in ribosome biogenesis, of which cancer cells can become addicted to in order to produce sufficient amounts of proteins for cell proliferation. Recently, the nucleolus has emerged as a central regulatory hub in many other cancer-relevant processes, including stress sensing, DNA damage response, cell cycle control, and proteostasis. This fostered the idea that nucleolar processes can be exploited in cancer therapy. Interestingly, a significant proportion of poly(ADP-ribose) polymerase 1 (PARP1) molecules are localized in the nucleolus and PARP1 also plays crucial roles in many processes that are important in cancer biology, including genome maintenance, replication, transcription, and chromatin remodeling. Furthermore, during the last years, PARP1 came into focus in oncology since it represents a promising target of pharmacological PARP inhibitors in various types of cancers. Here, we provide an overview of our current understanding on the role of PARP1 in nucleolar functions and discuss potential implications in cancer biology and therapy.

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Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age

Cited by 141 publications

References 121 publications

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription

The Nucleolus and PARP1 in Cancer Biology

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