Editors' ChoiceCancer

Shiva the Destroyer: Targeting the Destruction of RNA Polymerase for Cancer Treatment

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Science Translational Medicine  29 Jan 2014:
Vol. 6, Issue 221, pp. 221ec21
DOI: 10.1126/scitranslmed.3008473

In Hinduism, Shiva is the supreme deity—the destroyer or the transformer—capable of both benevolence and destruction. Now, Peltonen and colleagues develop a small molecule–based approach to target for destruction RNA polymerase I, a key enzyme essential to the production of ribosomal RNA (rRNA), which is the major component of the eukaryotic ribosome, the creator of proteins.

By performing a high-throughput screen of synthetic chemical libraries by using p53 transcriptional output as a readout, the authors identified the small molecule BMH-21 and found that it had a therapeutic index greater than 90 for cancer cell lines as compared with normal cell lines. Consistent with these observations, tumors in animals treated with BMH-1 were significantly smaller than tumors in control animals. BMH-21 intercalates into the DNA without causing DNA damage—a property that is unique in this structural/functional drug class. The authors found that BMH-21 intercalated into GC-rich regions of the DNA—specifically, rDNA sequences—and determined that drug binding to these regions inhibited Pol I activity. BMH-21 treatment of cells caused both altered nucleolar structures and mislocalization of nucleolar proteins. These effects resulted in a marked reduction in nascent RNA synthesis and were linked to the degradation of RPA194 (a key component of RNA polymerase I complex).

Combined, these studies identify a compound with a new mechanism of action that could possess broad anticancer activity in a wide range of histologically diverse tumor types. In the end, much like Shiva, BMH-21 can both destroy and transform.

K. Peltonen et al., A targeting modality for destruction of RNA polymerase I that possesses anticancer activity, Cancer Cell 25, 77–90 (2014). [Abstract]

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