Abstract
Triple negative breast cancer (TNBC) is currently the only group of breast cancers without an effective targeted therapy. Marine sponges have historically been a source of compounds with anticancer activity. In this study, we screened extracts from twenty marine sponges collected off the coast of Western Australia for cytotoxic activity against TNBC cells. One very active extract derived from the sponge Monanchora viridis was selected for bioactivity-guided fractionation. Through multiple steps of purification, we isolated a potent cytotoxic compound, which was identified as crambescidin 800 (C800). We found that C800 exhibited cytotoxic potency in a panel of breast cancer cells, of which TNBC and luminal cancer cell models were the most sensitive. In addition, C800 induced cell cycle arrest at the G2/M phase, resulting in a decline in the expression of cyclin D1, CDK4, and CDK6 in TNBC cells. This effect was associated with the inhibition of phosphorylation of Akt, NF-κB, and MAPK pathways, resulting in apoptosis in TNBC cells.
Highlights
Breast cancer is the most common malignancy among women worldwide [1,2]
We investigated the cytotoxic activity against Triple negative breast cancer (TNBC) cells with crude solvent extracts of sponges collected off the coast of Western Australia and stored in the Western Australian Marine Bioresources Library (WAMBL)
We studied the cell cycle analysis and the signaling pathways triggered by crambescidin 800 (C800) in TNBC cells and found that its cytotoxic effect is caused by cell cycle arrest at the G2/M phase, inhibition of cyclin D1, CDK4, and CDK6, and inhibition of phosphorylation of Akt/mammalian target of target of (mTOR), NF-κB, and mitogen-activated protein kinase protein (MAPK) pathways, leading to apoptosis in TNBC cells
Summary
Among various subtypes of breast cancer (Luminal A/B, basal-like and human epidermal growth receptor 2 (HER2). Enriched) identified by transcriptomic analyses of breast tumors, basal-like breast cancer is one of the most aggressive subtypes [3,4,5]. Basal-like breast cancers comprise a large fraction (~80%) of triple negative breast cancers (TNBC), which lack an estrogen receptor (ER), a progesterone receptor (PR), and HER2 [4]. These breast cancers do not have any targeted therapies available, unlike other breast cancer subtypes. TNBCs represent ~15% of all breast cancers, these tumors are characterised by poor differentiation, high proliferation, and metastatic behavior [6]. The treatment of choice for TNBC is standard chemotherapy, such as administration of taxanes (e.g., docetaxel), platinum agents (e.g., cisplatin), anthracyclines (e.g., doxorubicin), and antimetabolites (e.g., 5-fluorouracil) [7,8]
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