Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate.

Abstract

One of the major drawbacks of many of the currently used cancer drugs are off-target effects. Targeted delivery is one method to minimize such unwanted and detrimental events. To actively target lung cancer cells, we have developed a conjugate of the apoptosis inducing protein cytochrome c with transferrin because the transferrin receptor is overexpressed by many rapidly dividing cancer cells. Cytochrome c and transferrin were cross-linked with a redox sensitive disulfide bond for the intra-cellular release of the protein upon endocytosis by the transferrin receptor. Confocal results demonstrated the cellular uptake of the cytochrome c-transferrin conjugate by transferrin receptor overexpressing A549 lung cancer cells. Localization studies further validated that this conjugate escaped the endosome. Additionally, an in vitro assay showed that the conjugate could induce apoptosis by activating caspase-3. The neo-conjugate not only maintained an IC50 value similar to the well known drug cisplatin (50 μM) in A549 cancer cells but also was nontoxic to the normal lung (MRC5) cells. Our neo-conjugate holds promise for future development to target cancers with enhanced transferrin receptor expression.

• Authors: Manoj Saxena, Yamixa Delgado, Rohit Kumar Sharma, Shweta Sharma, Solimar Liz Ponce De León Guzmán, Arthur D Tinoco, Kai Griebenow
• Journal: PloS one (PLoS One) Vol. 13 Issue 4 Pg. e0195542 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 29649293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Receptors, Transferrin
• Transferrin
• Cytochromes c
• Caspase 3
• Caspase 9

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cytochromes c (chemistry, metabolism, pharmacology, therapeutic use)
• Drug Carriers (chemistry, metabolism)
• Enzyme Activation
• Gene Expression Regulation, Neoplastic
• Humans
• Models, Molecular
• Protein Conformation
• Protein Transport
• Receptors, Transferrin (metabolism)
• Transferrin (chemistry, metabolism)