Minocycline, a putative neuroprotectant, co-administered with doxorubicin-cyclophosphamide chemotherapy in a xenograft model of triple-negative breast cancer

Abstract

Minocycline is purported to have neuroprotective properties in experimental models of some human neurologic diseases, and has therefore been identified as a putative neuroprotectant for chemotherapy-induced cognitive impairment (CICI) in breast cancer patients. However, because its mechanism of action is believed to be mediated through anti-inflammatory, anti-apoptotic, and anti-oxidant pathways, co-administration of minocycline with chemotherapeutic agents has the potential to reduce the efficacy of anticancer drugs. The objective of this study is to evaluate the effect of minocycline on the activity of the AC chemotherapeutic regimen (Adriamycin [doxorubicin], Cytoxan [cyclophosphamide]) in in vitro and in vivo models of triple-negative breast cancer (TNBC). Clonogenic and methylthiazol tetrazolium (MTT) assays were used to assess survival and viability in two TNBC cell lines treated with increasing concentrations of AC in the presence or absence of minocycline. Biomarkers of apoptosis, cell stress, and DNA damage were evaluated by western blot. The in vivo effects of AC and minocycline, each alone and in combination, were assessed in a xenograft model of TNBC in female athymic nude mice by weekly tumor volume measurement, body and organ weight measurement, and histopathology. Apoptosis and proliferation were characterized by immunohistochemistry in the xenografts tumors. Brains from tumor-bearing mice were evaluated for microglial activation, glial scars, and the proportion of neural progenitor cells. Data from these in vitro and in vivo studies demonstrate that minocycline does not diminish the cytotoxic and tumor-suppressive effects of this chemotherapeutic drug combination in TNBC cells. Moreover, minocycline appeared to prevent the reduction in doublecortin-positive neural progenitor cells observed in AC-treated mice. We posit that minocycline may be useful clinically for its reported neuroprotective activity in breast cancer patients receiving AC without loss of chemotherapeutic efficacy.

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

“…Female athymic nude mice were subcutaneously injected with MDA-MB-231 cells (5*10 5 cells/0.1 ml/mouse) into the right flank of the mice, followed by the administration of a single intravenous injection of DOX (5 mg/kg) + CPP (10 mg/kg). H&E staining and immunohistochemistry analysis showed decreased DCX-positive cell expression compared to tumor control, which signifies the neural plasticity impairments in the chemotherapy-treated tumor mice (Himmel et al 2016).…”

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

“…In addition this, this drug reduced global DNA methylation and increased DNA hydroxymethylation in the prefrontal cortex of female mice [60]. Administration of doxorubicin-cyclophosphamide chemotherapy in a xenograft mice model of triple-negative breast cancer induces DNA damage as measured by the phosphorylation of the Ser-139 residue of the histone variant H2AX [61], forming γH2AX, an early cellular response to the induction of DNA doublestrand breaks. Detection of this phosphorylation event is considered an highly specific and sensitive molecular marker for monitoring DNA damage [62].…”

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors

“…While LY255283 is a leukotriene B4 receptor antagonist, Minocycline and Silibinin both target ALOX5, which plays a key role in the synthesis of leukotrienes from arachidonic acid [38]. Minocycline hydrochloride improves the blood-brain barrier, prevents the extravasation of breast cancer cells, and can be coadministered with doxorubicin-cyclophosphamide therapy without a loss of efficacy [39,40]. Silibinin is a flavonoid antioxidant from milk thistle with the potential to inhibit growth, arrest the cell cycle, and induce of apoptosis in several types of cancer cells, including BC [41].…”