Format

Send to

Choose Destination
J Nat Prod. 2011 Apr 25;74(4):567-73. doi: 10.1021/np100429s. Epub 2011 Feb 24.

The selectivity of austocystin D arises from cell-line-specific drug activation by cytochrome P450 enzymes.

Author information

1
Makoto Life Sciences, Inc., 15 DeAngelo Drive, Bedford, Massachusetts 01730, USA.

Abstract

The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D's selective cytotoxic activity. Here we show that the selective cytotoxic action of austocystin D arises from its selective activation by cytochrome P450 (CYP) enzymes in specific cancer cell lines, leading to induction of DNA damage in cells and in vitro. The potency and selectivity of austocystin D is lost upon inhibition of CYP activation and does not require MDR1 expression or activity. Furthermore, the pattern of cytotoxicity of austocystin D was distinct from doxorubicin and etoposide and unlike aflatoxin B(1), a compound that resembles austocystin D and is also activated by CYP enzymes to induce DNA damage. Theses results suggest that austocystin D may be of clinical benefit for targeting or overcoming chemoresistance.

PMID:
21348461
PMCID:
PMC3081663
DOI:
10.1021/np100429s
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center