The diarylheptanoid hirsutenone sensitizes chemoresistant ovarian cancer cells to cisplatin via modulation of apoptosis-inducing factor and X-linked inhibitor of apoptosis

Lee Farrand, Ji Young Kim, Sanguine Byun, Akechai Im-Aram, Jihoon Lee, Jeong Yong Suh, Ki Won Lee, Hyong Joo Lee, Benjamin K. Tsang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Cisplatin (CDDP) and its derivatives are considered first-line treatments for ovarian cancer (OVCA). However, despite initial results that often appear promising, in most cases patients will return with recurrent disease that fails to respond to further chemotherapy. We assayed a number of food phytochemicals with reported PI3K inhibitory ability to identify candidates that can influence CDDP treatment outcomes in chemoresistant OVCA cell lines. A direct comparison revealed that the diarylheptanoid hirsutenone from the tree bark of Alnus hirsuta var. sibirica was superior at inducing CDDP sensitivity in a number of chemoresistant cancer cell lines. Whereas hirsutenone treatment activated p53, its modest efficacy in p53-mutant and -null cell lines suggested the existence of a p53-independent mode of action. Further investigation revealed that hirsutenone causes CDDP-dependent apoptosis in chemoresistant cells by ubiquitin- proteasome-dependent X-linked inhibitor of apoptosis degradation and by enhancing the translocation of apoptosisinducing factor from the mitochondria to the nucleus. This was found to be, at least in part, under the influence of upstream Akt activity, linking hirsutenone-dependent PI3K inhibition with downstream effects on apoptosis-inducing factor, X-linked inhibitor of apoptosis, and apoptosis. Our findings provide rationale for further investigation of the effects of hirsutenone on chemoresistant OVCA in clinical studies.

Original languageEnglish
Pages (from-to)1723-1731
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number3
DOIs
Publication statusPublished - 2014 Jan 17

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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