title: 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.
authors.affiliation: Molecular Imaging Laboratory, MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Mehmet V
authors.initials: MV
authors.lastname: Yigit
authors.forename: Masashi
authors.initials: M
authors.lastname: Uchida
authors.forename: Alana W
authors.initials: AW
authors.lastname: Ross
authors.forename: Natalie
authors.initials: N
authors.lastname: Barteneva
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D004317:Doxorubicin
keywords: breast cancer; doxorubicin; nanodrug; pancreatic cancer; small interfering RNA