Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display - Cocktail

764 - SMA-tDodSNO improves the potency of doxorubicin in breast cancer evidence for the involvement of oxidative stress

Date

24 Nov 2018

Session

Poster display - Cocktail

Presenters

Houman Alimoradi

Citation

Annals of Oncology (2018) 29 (suppl_9): ix23-ix27. 10.1093/annonc/mdy430

Authors

H. Alimoradi1, A. Barzegarfallah1, K.F. Giresh2

Author affiliations

  • 1 Pharmacology And Toxicology, School of Medical Sciences; University of Otago, 9054 - Dunedin/NZ
  • 2 Aljawhara Center For Molecular Medicine, Arabian Gulf University, Manama - Bahrain/BH
More

Resources

Abstract 764

Background

When nitric oxide (NO) donor drugs combine with doxorubicin they potentiate doxorubicin, anticancer effects. However, limited NO payloads, too rapid NO release, and the lack of organ or tissue specificity have limited the clinical utility of currently available NO donors. Hence, there is a great need to design tuneable NO donors which can enhance the efficacy of currently available chemotherapeutic drugs such as doxorubicin.

Methods

A highly stable NO-releasing compound was synthesized by nitrosation of hydrophobic and sterically hindered thiol to form tert-dodecane S-nitrosothiol (tDodSNO). It was then encapsulated in a polymer (SMA) to make stable and hydrophilic NO-releasing NPs (SMA-tDodSNO). The dose (1-100 μM) dependent cytotoxicity of SMA-tDodSNO alone or combined with doxorubicin on 4T1 (mouse breast cancer) cells were assessed by MTT and cell cycle analysis. In addition, the effect of SMA-tDodSNO and Dox were evaluated on mitochondrial oxidative stress, mitochondrial membrane potential, intracellular calcium level, and ERK1/2 activity.

Results

Incubation of 4T1 cells with SMA-tDodSNO at μM concentrations showed a concentration-dependent decrease in cell survival. When the NPs were combined with doxorubicin they significantly (p<0.001) increased the doxorubicin cytotoxicity. In addition, the combination significantly enhanced mitochondrial oxidative stress and mitochondrial membrane permeabilization when compared to only doxorubicin-treated cells. Evaluation of intracellular calcium level via calcium sensitive fluorophore (Indo-1) demonstrated that the SMA-tDodSNO caused a boost in the cytosolic calcium level and over-activation of ERK1/2 pathway and apoptosis.

Conclusions

We designed a novel NO-releasing nanoparticle, SMA-tDodSNO, which showed controlled NO release and significant cytotoxicity in 4T1 cells. When combined with doxorubicin it increased the anticancer potency of doxorubicin via enhanced mitochondrial oxidative stress and elevation of cytosolic calcium level.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

University of Otago.

Funding

University of Otago.

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings