Doxorubicin Revisited

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Science  08 Feb 2013:
Vol. 339, Issue 6120, pp. 628
DOI: 10.1126/science.339.6120.628-b

Doxorubicin (Dox) is a chemotherapeutic drug with efficacy in many cancers, yet after 40 years of clinical use, there are lingering mysteries about its mechanism of action. The prevailing hypothesis is that Dox forms a complex with topoisomerase II, a DNA-unwinding enzyme, and this leads to DNA strand breaks that induce cell cycle arrest. Although much evidence supports this model, not all data are consistent with it. New insights into Dox's cellular effects could help optimize its antitumor activity, reduce its adverse side effects, and/or help oncologists identify which patients are most likely to respond to the drug.

Denard et al. propose that the membrane-associated transcription factor CREB3L1 plays a key role in Dox's antitumor activity. In cultured cells, Dox increased synthesis of the lipid ceramide, which in turn caused proteolytic activation of CREB3L1 and its entry into the nucleus, where it increased transcription of cell cycle—inhibitory genes. When CREB3L1 levels were experimentally suppressed, cancer cells became resistant to Dox. These results suggest that CREB3L1 may be a biomarker of Dox-responsive cancer cells or even a druggable target itself.

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