Abstract
BC-11 is an easily synthesized simple thiouronium-substituted phenylboronic acid, which has been shown to be cytotoxic on triple negative MDA-MB231 breast cancer cells by inducing a perturbation of cell cycle when administered at a concentration equal to its ED50 at 72 h (117 μM). Exposure of cells to BC-11, either pre-absorbed with a soluble preparation of the N-terminal fragment of urokinase-plasminogen activator (uPa), or in co-treatment with two different EGFR inhibitors, indicated that: (i) BC-11 acts via binding to the N-terminus of the enzyme where uPa- and EGF receptor-recognizing sites are present, thereby abrogating the growth-sustaining effect resulting from receptor binding; and (ii) the co-presence of the EGFR inhibitor PD153035 potentiates BC-11’s cytotoxicity. Exposure of cells to a higher concentration of BC-11 corresponding to its ED75 at 72 h (250 μM) caused additional impairment of mitochondrial activity, the production of reactive oxygen species and promotion of apoptosis. Therefore, BC-11 treatment appears to show potential for the development of this class of compounds in the prevention and/or therapy of “aggressive” breast carcinoma.
Highlights
It is known that treatment of triple-negative breast cancer (TNBC) faces limited options due to the absence of expression of estrogen and progesterone receptors and human epidermal growth factor receptor 2 by neoplastic cells, which accounts for the dearth of targeted therapies, elevated tumor aggressiveness and poor patient prognosis [1]
The results indicate that BC-11 may be included in the list of drug-like molecules capable of inducing cytotoxicity on TNBC cells “in vitro”
Error bars correspond to s.e.m. of three independent measurements; (B) Combination Index (CI) values of BC-11 in two-drug and three-drug associations with the EGF receptor (EGFR) inhibitors 3-B and 4-B at different effect dose levels
Summary
It is known that treatment of triple-negative breast cancer (TNBC) faces limited options due to the absence of expression of estrogen and progesterone receptors and human epidermal growth factor receptor 2 by neoplastic cells, which accounts for the dearth of targeted therapies, elevated tumor aggressiveness and poor patient prognosis [1]. To this end, a gamut of non-targeted treatment approaches have been investigated, including the use of anti-angiogenetic drugs, tyrosine kinase and PARP inhibitors. Our goal was to comprehensively examine the effects of BC-11 on an “in vitro” model system of TNBC, i.e., MDA-MB231 cells, with respect to viability and proliferation via a MTT assay, flow cytometric evaluation of cell cycle distribution, apoptosis modulation, and mitochondrial metabolic state
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