Simultaneous defeat of MCF7 and MDA-MB-231 resistances by a hypericin PDT\u2013tamoxifen hybrid therapy

Theodossis A Theodossiou,Mantas Grigalavicius,Qian Peng,Beata Grallert,Else Marit Inderberg,Sébastien Wälchli,Cathrine E Olsen,Pierre Dillard,Andreas Kubin,Kay Oliver Schink,Kristian Berg,Muhammad Ali

doi:10.1038/s41523-019-0108-8

Theodossis A Theodossiou, Mantas Grigalavicius + Show 10 more

Open Access

https://doi.org/10.1038/s41523-019-0108-8

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Journal: NPJ breast cancer	Publication Date: Apr 10, 2019
Citations: 88	License type: open-access

Affiliation: Oslo University Hospital

Abstract

Currently the greatest challenge in oncology is the lack of homogeneity of the lesions where different cell components respond differently to treatment. There is growing consensus that monotherapies are insufficient to eradicate the disease and there is an unmet need for more potent combinatorial treatments. We have previously shown that hypericin photodynamic therapy (HYP-PDT) triggers electron transport chain (ETC) inhibition in cell mitochondria. We have also shown that tamoxifen (TAM) enhances cytotoxicity in cells with high respiration, when combined with ETC inhibitors. Herein we introduce a synergistic treatment based on TAM chemotherapy and HYP-PDT. We tested this novel combinatorial treatment (HYPERTAM) in two metabolically different breast cancer cell lines, the triple-negative MDA-MB-231 and the estrogen-receptor-positive MCF7, the former being quite sensitive to HYP-PDT while the latter very responsive to TAM treatment. In addition, we investigated the mode of death, effect of lipid peroxidation, and the effect on cell metabolism. The results were quite astounding. HYPERTAM exhibited over 90% cytotoxicity in both cell lines. This cytotoxicity was in the form of both necrosis and autophagy, while high levels of lipid peroxidation were observed in both cell lines. We, consequently, translated our research to an in vivo pilot study encompassing the MDA-MB-231 and MCF7 tumor models in NOD SCID-γ immunocompromised mice. Both treatment cohorts responded very positively to HYPERTRAM, which significantly prolonged mice survival. HYPERTAM is a potent, synergistic modality, which may lay the foundations for a novel, composite anticancer treatment, effective in diverse tumor types.

Highlights

All scientific efforts to find a cure for cancer stumble across one obstacle, simple yet difficult to circumvent: cancerous cells come from random mutations of normal cells, in an effort to escape the tight controls imposed on them
We evaluated the combination of HYPPDT and TAM administration (HYPERTAM) to compare how the combinatorial treatment affected the two cell lines in vitro and in vivo in animal MCF7 and MDA-MB-231 tumor models and whether there were any synergistic effects in either of the two cell lines
The micrographs reveal a close localization of HYP and NDMTAM-FITC in MDA-MB-231 cells, with NDMTAM colocalizing very well with Mitotracker® Deep Red both in MCF7 and MDA-MB-231 cell lines (Fig. S2)

Summary

Introduction

All scientific efforts to find a cure for cancer stumble across one obstacle, simple yet difficult to circumvent: cancerous cells come from random mutations of normal cells, in an effort to escape the tight controls imposed on them. In the case of MCF7 (Fig. 1a) HYP-PDT induced a 50% reduction in viability at 24h after treatment, which was reduced to ~30% at 48 h probably due to cell re-proliferation.

Results

Conclusion