Combination Suicide Gene Delivery with an Adeno-Associated Virus Vector Encoding Inducible Caspase-9 and a Chemical Inducer of Dimerization Is Effective in a Xenotransplantation Model of Hepatocellular Carcinoma.
Nusrat Israr KhanSridhar BammidiSourav ChattopadhyayGiridhara R JayandharanPublished in: Bioconjugate chemistry (2019)
Current treatment approaches for hepatocellular carcinoma (HCC) have a narrow therapeutic index and alternate modes of treatment are thus required. We have utilized a gene delivery vector containing inducible caspase 9 (iCasp9) gene, which is a synthetic analogue based on the mammalian caspase 9 and fused to a human FK506 binding protein that allows its conditional dimerization to a synthetic, small molecule [chemical inducer of dimerization, AP20187] and results in target cell apoptosis. In our studies, we have tested these synthetic vectors based on an adeno-associated virus platform for their potential anti-tumorigenic effect in human HCC cells in vitro and in a HCC tumor model developed in nude mice. Our data demonstrates that the iCasp9-AP20187 bioconjugate is able to trigger terminal effectors of cellular apoptosis and presents a viable approach for the potential treatment of HCC.
Keyphrases
- induced apoptosis
- small molecule
- cell death
- endothelial cells
- cell cycle arrest
- endoplasmic reticulum stress
- oxidative stress
- binding protein
- transcription factor
- cell proliferation
- gene expression
- metabolic syndrome
- combination therapy
- adipose tissue
- signaling pathway
- risk assessment
- machine learning
- induced pluripotent stem cells
- replacement therapy
- protein protein