Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance.

BACKGROUND: Doxorubicin (DOX) is the most widely used chemotherapeutic agent that has multimodal cytotoxicity. The main cytotoxic actions of DOX occur in the nucleus. The emergence of drug-resistant cancer cells that have the ability to actively efflux DOX out of the nucleus, and the cytoplasm has led to the search for a more effective derivative of this drug. MATERIALS AND METHODS: We created a new derivative of DOX that was derived via simple conjugation of the 3' amino group of DOX to the dexamethasone molecule. RESULTS: Despite having a lower cytotoxic activity in MCF-7 cells, the conjugated product, DexDOX, exerted its actions in a manner that was different to that of DOX. DexDOX rapidly induced MCF-7 cell apoptosis without entering the nucleus. Further analysis showed that Dex-DOX increased cytosolic oxidative stress and did not interfere with the cell cycle. In addition, the conjugated product retained its cytotoxicity in multidrug resistance-1-overexpressing MCF-7 cells that had an approximately 16-fold higher resistance to DOX. CONCLUSION: We have synthesized a new derivative of DOX, which has the ability to overcome multidrug resistance-1-induced resistance. This molecule may have potential as a future chemotherapeutic agent.

Efficient ZFN-Mediated Stop Codon Integration into the CCR5 Locus in Hematopoietic Stem Cells: A Possible Source for Intrabone Marrow Cell Transplantation.

We reported a simple genome editing approach that can generate human immunodeficiency virus-1 (HIV) coreceptor defective cells, which may be useful for latent viral eradication treatment. Samples of bone marrow leftover after diagnostic procedures and crude bone marrow from aviremic HIV patients were subjected to zinc finger nuclease-mediated stop codon insertion into chemokine receptor 5 (CCR5) loci. Locked nucleic acid-based polymerase chain reaction was used to estimate the amount of insertion in the expandable CD34+ cells. The results showed that about 0.5% of CD34+ cells carried stop codon insertions in CCR5 loci. Cells edited using this simple protocol have the potential to be infused back into the bone marrow.