2310P - Oxygen nano-bubbles attenuate hypoxia-induced tumour malignancy in tumour xenograft models

Background

The rapid proliferation of cancer cells leads to abnormal vascularization, creating a hypoxic tumor core in most advanced solid tumors. Recent studies have shown that hypoxia is associated with poor prognosis in cancer patients. Tumor aggressiveness is driven by hypoxia, which confers resistance to many conventional cancer therapies. In the present study, we propose that oxygen nanobubbles can reduce the hypoxic effect on the epithelial-to-mesenchymal transition (EMT) and prevent migration and invasion in non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

Methods

Using the sonic cavitation method, we have developed a method to generate bulk oxygen nanobubbles (ONBs) with dipalmitoyl phosphatidylcholine (DPPC) lipid and quantitate mean diameter and number density through nanoparticle tracking analysis and insight. We have treated A549 lung adenocarcinoma and MDA-MB-231 triple-negative breast cancer cell lines with 1% oxygen and ONB. We have also checked its preventive role in the zebrafish tumor xenograft model. We have measured HIF-1a and EMT expression markers by immunoblot and qPCR analysis. Moreover, we have used the 4T1 BALB/c mice tumor xenograft model for further confirmation.

Results

ONB promotes HIF-1α hydroxylation and its proteasomal degradation in hypoxic cancer cells. ONBs treated A549 and MDA-MB-231 cancer cells and an adult zebrafish A549 tumor xenografts showed the downregulation of TGF-β and VEGFA expression at the transcriptional and translational levels, which also led to upregulation of epithelial genes like E-cadherin with down-regulation of mesenchymal genes like N cadherin, Vimentin, Fibronectin. ONB treatment significantly affects cancer cell migration. Also, liposomal ONB administrated 4T1 BALB/c breast tumor xenograft model showed similar results.

Conclusions

ONBs reduce HIF-1 mediated epithelial to mesenchymal transition (EMT) controlled by TGF-b and VEGFA and prevent cellular migration and invasion in solid tumors, particularly NSCLC and TNBC. In conclusion, targeted administration of ONB could be a better therapeutic approach to inhibit the hypoxic detrimental effect, which helps to increase the efficacy of anticancer treatments.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Department of Science and Technology (DST) Project, India (DSTSERB- ECR/2016/000288Department of Science and Technology (DST) Project, India (DSTSERB- DST (Department of Science and Technology) Project India, ECR/2016/000288.

Disclosure

All authors have declared no conflicts of interest.