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Sequence-dependent combination therapy with doxorubicin and a survivin-specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma.

Abstract
The clinical management of cancer reflects a balance between treatment efficacy and toxicity. While typically, combination therapy improves response rate and time to progression compared with sequential monotherapy, it causes increased toxicity. Consequently, in cases of advanced cancer, emerging guidelines recommend sequential monotherapy, as a means to enhance quality of life. An alternative approach that could overcome nonspecific toxicity while retaining therapeutic efficacy, involves the combination of chemotherapy with targeted therapy. In the current study, we tested the hypothesis that combination therapy targeting survivin (BIRC5) and low-dose doxorubicin (Dox) will show enhanced therapeutic potential in the treatment of cancer, as compared to monotherapy with Dox. We demonstrate in both in vitro and in vivo models of breast cancer that combination therapy with a low dose of Dox and an anti-survivin siRNA nanodrug (MN-siBIRC5) is superior to mono-therapy with either low- or high-dose Dox alone. Importantly, therapeutic efficacy showed prominent sequence dependence. Induction of apoptosis was observed only when the cells were treated with Dox followed by MN-siBIRC5, whereas the reverse sequence abrogated the benefit of the drug combination. In vivo, confirmation of successful sequence dependent combination therapy was demonstrated in a murine xenograft model of breast cancer. Finally, to determine if the observed effect is not limited to breast cancer, we extended our studies to a murine xenograft model of pancreatic adenocarcinoma and found similar outcomes as shown for breast cancer.
AuthorsSubrata K Ghosh, Mehmet V Yigit, Masashi Uchida, Alana W Ross, Natalie Barteneva, Anna Moore, Zdravka Medarova
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 134 Issue 7 Pg. 1758-66 (Apr 1 2014) ISSN: 1097-0215 [Electronic] United States
PMID24114765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2013 UICC.
Chemical References
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Doxorubicin
Topics
  • Adenocarcinoma (drug therapy, genetics)
  • Animals
  • Breast Neoplasms (drug therapy, genetics)
  • Cell Line, Tumor
  • Combined Modality Therapy (methods)
  • Doxorubicin (pharmacology)
  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins (genetics)
  • Mice
  • Nanoparticles (administration & dosage)
  • Pancreatic Neoplasms (drug therapy, genetics)
  • RNA, Small Interfering (genetics)

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