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

Subrata K. Ghosh, Mehmet V. Yigit, Masashi Uchida, Alana W. Ross, Natalie Barteneva, Anna Moore, Zdravka Medarova

Research output: Contribution to journalArticle

21 Citations (Scopus)

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. What's new? Standard combination chemotherapy can overcome drug resistance and delay cancer progression, but it is also more toxic than the use of single drugs alone. This study suggests, however, that combination therapy involving a chemotherapeutic agent and molecularly targeted therapy may have the ability to both retain therapeutic efficacy and preserve quality of life. In vitro and in vivo experiments reveal that sequence-dependent therapy with low-dose doxorubicin and an anti-survivin siRNA nanodrug can have profound effects on primary tumor growth and circumvent the issues of toxicity and morbidity associated with standard chemotherapy.

Original languageEnglish
Pages (from-to)1758-1766
Number of pages9
JournalInternational Journal of Cancer
Volume134
Issue number7
DOIs
Publication statusPublished - Apr 1 2014
Externally publishedYes

Keywords

  • breast cancer
  • doxorubicin
  • nanodrug
  • pancreatic cancer
  • small interfering RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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