Abstract
A novel plant sesquiterpene lactone derivative, DET derivative (DETD)-35, originating from parental deoxyelephantopin (DET) was previously observed to effectively suppress human triple negative breast cancer (TNBC) MDA-MB-231 cell activity and tumor growth in mice. In this study, the mechanisms underlying the activity of DETD-35 were elucidated. DET and DETD-35 induced reactive oxygen species (ROS) which caused structural damage and dysfunction of mitochondria and increased cytosolic calcium level, subsequently evoking exosome release from the cancer cells. Intriguingly, exosomes induced by both compounds had an atypical function. Cancer cell-derived exosomes commonly show metastatic potential, but upon DET/DETD-35 treatment exosomes showed anti-proliferative activity against MDA-MB-231 cells. Quantitative proteome analysis of TNBC cell-secreted exosomes showed that DET and DETD-35 attenuated the expression of proteins related to cell migration, cell adhesion, and angiogenesis. Furthermore, several exosomal proteins participating in biological mechanisms such as oxidative stress and decrease of transmembrane potential of mitochondria were found deregulated by treatment with either compound. Pretreatment with ROS scavenger, N-acetylcysteine, blockaded DET- or DETD-35-induced oxidative stress and calcium dependent exosome release mechanisms, and also reverted DET- or DETD-35-induced reprogramming exosomal protein expression profiles resulting in attenuation of exosomal toxicity against TNBC cell proliferation. In summary, this study shows that a plant-derived sesquiterpene lactone DET and its analog DETD-35 inhibitory TNBC cell activities through oxidative stress-induced cancer cell releasing exosomes in tandem with alteration of exosomal protein composition and functions. The findings of this study suggest that DETD-35 may be suitable for further development into an anti-TNBC drug.
Highlights
Triple negative breast cancer (TNBC) is a breast cancer subtype lacking expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) and accounts for about 15–25% of total breast cancer patients (Jamdade et al, 2015)
A growing body of evidence indicates that exosomes mediate the delivery of proteins, mRNAs, and miRNAs from cancer cells to recipient or neighboring cells by cell-to-cell communication, which may assist in the creation of a metastatic niche and facilitate cancer cell progression and metastasis, or influence the activity and/or behaviors of recipient cells (O’Brien et al, 2013; Costa-Silva et al, 2015)
We observed that the germacranolide sesquiterpene lactone DET and its derivative DET derivative (DETD)-35 significantly induced the release of exosomes from MDA-MB-231 cells into media compared to the vehicle−treated cells, and a significant secretion flux was observed at 8-h treatment
Summary
Triple negative breast cancer (TNBC) is a breast cancer subtype lacking expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) and accounts for about 15–25% of total breast cancer patients (Jamdade et al, 2015). Since the tumor cells are deficient in the necessary receptors, common hormone therapy or target therapies are inefficient, and a combination of chemotherapy drugs are often used on TNBC patients; such a therapeutic approach cannot circumvent chemotherapy-induced drug resistance and adverse side effects in cancer patients (Chougule et al, 2011; von Minckwitz and Martin, 2012). There is need to develop novel intervention approaches or therapeutic agents with minimal toxicities or better efficacy for TNBC patients. Pancreatic cancer-derived exosomes promote liver metastasis by generating an immune cell infiltrated fibrotic microenvironment that favors metastasis (Zhang and Wang, 2015). Deciphering a cell-type specific set of exosomal proteins may offer an ideal option for the development of exosome-based biomarkers and therapies. Exosomes possess the ability to cross biological barriers; exosome-encapsulated drug or bioactive natural product formulation are considered to be a versatile strategy for treating cancers or other inflammatory disorders (Zhuang et al, 2011; Haney et al, 2015; Ha et al, 2016)
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