Nonviral nanoscale-based delivery of antisense oligonucleotides targeted to hypoxia-inducible factor 1 alpha enhances the efficacy of chemotherapy in drug-resistant tumor.

Abstract

PURPOSE:

To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1 alpha (HIF1A).

EXPERIMENTAL DESIGN:

The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis.

RESULTS:

The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy.

CONCLUSIONS:

The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.

• Authors: Yang Wang, Maha Saad, Refika I Pakunlu, Jayant J Khandare, Olga B Garbuzenko, Alexandre A Vetcher, Viatcheslav A Soldatenkov, Vitaly P Pozharov, Tamara Minko
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 11 Pg. 3607-16 (Jun 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18519795 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Oligonucleotides, Antisense
• Doxorubicin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Blotting, Western
• Cell Line, Tumor
• Doxorubicin (administration & dosage)
• Drug Delivery Systems (methods)
• Drug Resistance, Neoplasm
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects)
• Mice
• Microscopy, Atomic Force
• Microscopy, Electron, Transmission
• Nanoparticles
• Oligonucleotides, Antisense (administration & dosage)
• Ovarian Neoplasms (drug therapy)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays