No abstract

Triple-negative breast cancer is an aggressive subtype of breast cancer with low 5-year survival rates, high 3-year recurrence rates, and no known therapeutic targets. Recent studies have indicated that triple-negative breast cancers possess an altered metabolic state with higher rates of glycolysis, mitochondrial oxidative phosphorylation, and increased generation and utilization of tricarboxylic acid cycle intermediates. Here, we utilized label-free quantitative proteomics to gain insight into the anticancer mechanisms of a methanolic extract from the Central American plant Lippia origanoides on MDA-MB-231 triple-negative breast cancer cells. The L. origanoides extract dysregulated mitochondrial oxidative phosphorylation by suppressing the expression of several subunits of Complex I of the electron transport chain, and inhibited cellular metabolism by down-regulating key tricarboxylic acid cycle enzymes and mitochondrial lipid and amino-acid metabolic pathways. Our study also revealed that treatment with the extract activated the stress response and pathways related to cell-cycle progression and DNA repair. Overall, our results reveal compelling new evidence that the extract from L. origanodes triggers rapid irreversible apoptosis in MDA-MB-231 cells by effectively 'starving' the cells of metabolites and ATP. We continue to study the specific bioactive components of the extract in the search for novel, highly effective mitochondrial inhibitors to selectively target triple-negative breast cancer.

Treatments targeting hormone receptors typically fail to provide a positive clinical outcome against triple-negative breast cancers (TNBC), which lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu). Towards identifying viable treatments for aggressive breast cancer, we have tested an extract of the tropical plant Lippia origanoides (LOE) on TNBC and normal cells lines to uncover its potential anticancer effects. Treatment with LOE reduced TNBC cell viability in a dose-dependent manner to a greater extent than in normal mammary epithelial MCF10A cells. In MDA-MB-231 cells, LOE was found to halt the cell cycle in the G0/G1 phase via cyclin D1 and cIAP2 regulation, and induce apoptosis without promoting necrosis via caspase-8/-3 and PARP cleavage. Constitutive nuclear factor-κB (NF-κB) signaling has been shown to contribute to the heightened inflammatory state and survival in TNBC cells. Herein, we also provide evidence that LOE inhibits NF-κB signaling by reducing RIP1 protein levels in MDA-MB-231 cells. These studies reveal that LOE suppresses key features of the progression of aggressive breast cancer cells and provides a basis for further definition of its underlying mechanisms of action and anticancer potential.

No abstract

Cancer is a disease of cell cycle, characterized by uncontrolled cell division. The tumor suppressor gene p53 plays a major role in cell cycle control, blocking the cell progression at G 1 /S phases. In triple negative breast cancer (TNBC), the lack/mutation of p53 is a common genetic irregularity that promotes survival signals leading to tumorigenesis. Due to its unique molecular profile, aggressive behavior, and metastasis, no targeted therapies exist for TNBC. This motivates our exploration of the influence of Electro-Curcumin-Therapy on the viability, cell cycle and p53 expression profile of TNBC cells. MDA-MB-231, human TNBC cells were treated with curcumin and eight 200 V cm −1 electric pulses (EPs) of either 100 μs or 5 ms duration. The synergy of 5 ms EPs and curcumin reduced viability to as low as 6% at 48 h after treatment. Combining the 100 μs EPs with curcumin arrested 80% cells in the G 0 /G 1 phase. Applying 5 ms EPs with curcumin caused cells to shift from the G 2 phase (9% reduction) to the S phase population (21% increase) compared to control. Combining 100 μs EPs with curcumin significantly downregulated the p53 level, while the p53 level significantly increased for 5 ms EPs with and without curcumin. These results indicate the potent effect of combining EPs and curcumin to effectively cause cell death in TNBC cells with different mechanistic behaviors, while having a much-reduced impact on cell death in normal mammary cells.