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

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.

SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice

“…Our data point out a new “metabolic” function of this NAD + -dependent deacetylase in BC cells, which consists of SIRT6’s ability to enhance PDH expression and activity, OXPHOS, and ATP availability in BC cells. Quite remarkably, SIRT6 overexpression also increased oxygen consumption and ATP synthase activity in MDA-MB-231 cells, which is normally considered to be a glycolysis-dependent cell line, as opposed to other BC cells, which primarily rely on OXPHOS for their metabolism, including MCF7 cells [ 42 ].…”

Photodynamic Efficacy of Cercosporin in 3D Tumor Cell Cultures

“…In our previous work (13) using a similar naturally occurring perylenequinone PS, hypericin (HYP), we found that HYP‐PDT damages irreversibly complex III of the ETC in DU145, human prostate carcinoma cells. In a more recent publication (14), we further saw that HYP‐PDT caused a profound decrease of both the respiration and the glycolytic rate of MCF7 human breast adenocarcinoma cells, 1 h following irradiation. This is in good agreement with our 2D cerco findings (5), where cerco‐PDT collapsed the respiration and profoundly diminished the glycolytic action in U87, T98G human glioblastoma multiforme and MCF7 human breast carcinoma cells.…”

Analysis of TCGA data of differentially expressed EMT‑related genes and miRNAs across various malignancies to identify potential biomarkers

“…Indeed, although they are both invasive ductal breast carcinoma cells, they have a number of phenotypic and genotypic differences. MCF-7 are estrogen receptor-positive cells, whereas MDA-MB-231 cells are estrogen and progesterone receptor-negative; in addition, MCF-7 cells express the epithelial phenotype in contrast to the MDA-MB-231 cells that are more mesenchymal (30)(31)(32). Similarly, as shown in Fig.…”