A Subset of Platinum-containing Chemotherapeutic Agents Kills Cells by Inducing Ribosome Biogenesis Stress

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2017 Mar 7

PMID 28263311

Citations 203

Authors

Peter M Bruno

Yunpeng Liu

Ga Young Park

Junko Murai

Catherine E Koch

Timothy J Eisen

Justin R Pritchard

Yves Pommier

Stephen J Lippard

Michael T Hemann

Affiliations

Soon will be listed here.

Abstract

Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.

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