How does doxorubicin work?

Abstract

A new mechanism involving cleavage of a transcription factor called CREB3L1 has been proposed to explain the anti-tumour effects of doxorubicin.

Keywords: CREB3L1; Human; cancer; ceramide; doxorubicin.

Figure 1.

Understanding how the anticancer drug doxorubicin works is an important challenge in cancer research. Two independent groups have recently published evidence for two potential mechanisms that might be able to explain anti-tumour effects of doxorubicin. Zhang et al. showed diminished toxicity in cardiomyocytes from mice lacking the Top2b gene. These data are consistent with previous claims that doxorubicin helps to stabilize complexes containing double-stranded DNA and the enzyme topoisomerase II (top right of figure): this enzyme then cuts both of the DNA strands, which leads to the death of both normal cells (predominantly via topoisomerase IIβ) and in tumour cells that are susceptible to the drug (predominantly via topoisomerase IIα), thus accounting for both the toxicity and anti-tumour efficacy of doxorubicin. Denard et al. propose that doxorubicin increases the production of ceramides inside cells (top left), which leads to the latent transcription factor CREB3L1 translocating from the endoplasmic reticulum to the Golgi apparatus. Two proteases (S1P and S2P) then cut the CREB3L1 protein; and its amino-terminal fragment then migrates into the nucleus, where it acts as a transcription factor to activate the CDNK1A locus and additional genes (bottom right). This leads to increased expression of the p21 protein along with other proteins that inhibit the proliferation of tumour cells.