Introduction/Aim: Cancer is one of the prevailing causes of death worldwide. The prognosis of this disease is poor and may be attributed by high rates of mutations leading to heterogeneity of tumours, requiring an invariant target that selectively combats malignant cells. Novel mitochondrial targeting anti-cancer agents, mitocans, are often selective for cancer cells and may induce apoptosis in resistant cancers, such as HER2high breast carcinomas. Tamoxifen is a potent agent used to treat breast cancers. However, it is inefficient to HER2high breast tumours. Thus, our lab focused on a novel mitocan compound, MitoTAM, to target resistant breast cancers with higher efficacy.
Methods: MCF-7 cells with varying amounts of HER2 were used. The effect of treatment with MitoTAM was assessed by MTT assay, flow cytometry, and western blotting. HER2 localisation was evaluated by fractionation and immunofluorescence staining. FVB/N c-neu mice were treated with mitochondrial targeting compound and tumour volume was evaluated by ultrasound imaging.
Results: We show that HER2high cells were more sensitive to MitoTAM treatment at a 10 times lower dose compared to tamoxifen. HER2high cells treated with MitoTAM triggered the apoptotic pathway, upregulating Bax and downregulating Bcl-2. FVB/N c-neu mice treated with MitoTAM showed a significant decrease in tumour volume, a 70% reduction in tumour mass, and up-regulation of Bax and cleaved caspase-3. Interestingly, we observed HER2 to be highly expressed in the mitochondria of HER2high cells and tumours.
Conclusion: We found that MitoTAM is more sensitive to HER2high cells and induces the intrinsic apoptotic pathway. A remarkable decrease in tumour growth was observed with MitoTAM treatment, suggesting MitoTAM to be an effective anti-cancer agent. We also show that HER2 is highly expressed in mitochondria of HER2high cells and tumours. However, the mechanism of HER2 translocation to mitochondria is yet to be evaluated.