Abstract
Triple-negative tumor cells, a malignant subtype of breast cancer, lack a biologically targeted therapy. Given its DNA repair inhibiting properties, caffeine has been shown to enhance the effectiveness of specific tumor chemotherapies. In this work, we have investigated the effects of caffeine, cisplatin, and a combination of the two as potential treatments in energy metabolism for three cell lines, triple-negative breast cancer (MDA-MB-231), estrogen-receptor lacking breast cancer (MCF7) and breast epithelial cells (MCF10A) using a sensitive label-free approach, phasor-fluorescence lifetime imaging microscopy (phasor-FLIM). We found that solely using caffeine to treat MDA-MB-231 shifts their metabolism towards respiratory-chain phosphorylation with a lower ratio of free to bound NADH, and a similar trend is seen in MCF7. However, MDA-MB-231 cells shifted to a higher ratio of free to bound NADH when cisplatin was added. The combination of cisplatin and caffeine together reduced the survival rate for MDA-MD231 and shifted their energy metabolism to a higher fraction of bound NADH indicative of oxidative phosphorylation. The FLIM and viability results of MCF10A cells demonstrate that the treatments targeted cancer cells over the normal breast tissue. The identification of energy metabolism alteration could open up strategies of improving chemotherapy for malignant breast cancer.
Highlights
According to the National Breast Cancer Foundation, breast cancer is the most common cancer diagnosed in women, and one in eight women will be diagnosed with breast cancer in their lifetime [1]
MDA-MB-231 is a known representative of triple-negative breast cancer, which has aggressive behavior as they go through reattachment, cell metastasis, and cell aggregation [3]
The aim of this paper is to characterize the enhancing effects of caffeine effects in altering energy metabolism to triple-negative breast cancer cells, which are characterized by a high frequency of mutations in ATM and BRCA2, as well as RB1 loss and cyclin E1 amplification [21,22]
Summary
According to the National Breast Cancer Foundation, breast cancer is the most common cancer diagnosed in women, and one in eight women will be diagnosed with breast cancer in their lifetime [1]. A subtype of breast cancer is basal-like breast cancer, known as triple-negative breast cancer (TNBC). MDA-MB-231 is a known representative of triple-negative breast cancer, which has aggressive behavior as they go through reattachment, cell metastasis, and cell aggregation [3]. There is a need for an effective therapy that treats triple-negative breast cancer [4,5]. Cisplatin is commonly used as a chemotherapy drug to treat different cancers today [6]. Cisplatin damages non-cancerous cells [10]. Despite the short-term results, the effectiveness of cisplatin declines as the cancer cells becomes more resistant to the drug [11]
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