title: 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.
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Himmel
authors.affiliation: Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Maryam B
authors.initials: MB
authors.lastname: Lustberg
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: A Courtney
authors.initials: AC
authors.lastname: DeVries
authors.affiliation: Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Poi
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: kulp.1@osu.edu.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000517:prevention & control; D003520:Cyclophosphamide / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008911:Minocycline / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms; D023041:Xenograft Model Antitumor Assays
chemical_list: D018696:Neuroprotective Agents; D004317:Doxorubicin; D003520:Cyclophosphamide; D008911:Minocycline
keywords: Chemo fog; Chemotherapy; Chemotherapy-induced cognitive impairment; Minocycline; Triple-negative breast cancer