A novel cancer therapy: combined liposomal hypoxia inducible factor 1 alpha antisense oligonucleotides and an anticancer drug.
The combined influence of doxorubicin (DOX) and liposomal antisense oligonucleotides (ASOs) targeted to hypoxia-inducible factor 1 alpha (HIF1A) subunit on the apoptosis signaling pathways and cellular pump and nonpump resistance were investigated. Drug-sensitive A2780 and multidrug-resistant A2780/AD human ovarian carcinoma cells were used. Cells were incubated within 48h in normoxic (21% O(2), 5% CO(2) and 74% N(2)) or hypoxic (1% O(2), 5% CO(2) and 94% N(2)) conditions, with or without DOX in the concentration corresponding to the IC(50) dose, with or without liposomal ASO targeted to HIF1A mRNA. Apoptosis induction, lactic acid concentration, expression of genes and proteins involved in apoptosis signaling pathways, pump and nonpump cellular resistance were assessed. The results showed that overexpression of HIF1A protein induced by exposure to hypoxia and DOX activated both apoptotic cellular signal and cellular antiapoptotic defense. In addition, while hypoxia suppressed cellular pump resistance, due to multidrug resistance-associated protein family transporters, DOX activated pump resistance. A decrease in the expression of targeted protein (HIF1A) by liposomal HIF1A ASO effectively suppressed pump and nonpump cellular resistance and significantly enhanced apoptosis induction by hypoxia and DOX. Data obtained showed that ASO targeted to HIF1A mRNA that suppress cellular antihypoxic defense might be used as a powerful tool to improve the anticancer action of cytotoxic drug or even as an anticancer agent.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
Yang
Y
Wang
Tamara
T
Minko
D017209:Apoptosis; D020169:Caspases / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D004338:Drug Combinations; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; D019344:Lactic Acid; D004317:Doxorubicin; D020169:Caspases