ABSTRACT
Despite recent advances in therapy, breast cancer remains the second most common cause of death from malignancy in women. Chemotherapy plays a major role in breast cancer management, and combining chemotherapeutic agents with nonchemotherapeutic agents is of considerable clinical interest. Cucurbitacins are triterpenes compounds found in plants of the Cucurbitaceae family, reported to have anticancer and anti-inflammatory activities. Previously, we have shown antiproliferative activity of cucurbitacin B (CuB) in breast cancer, and we hypothesized that combining CuB with chemotherapeutic agents can augment their antitumor effect. Here, we show that a combination of CuB with either docetaxel (DOC) or gemcitabine (GEM) synergistically inhibited the proliferation of MDA-MB-231 breast cancer cells in vitro. This antiproliferative effect was accompanied by an increase in apoptosis rates. Furthermore, in vivo treatment of human breast cancer orthotopic xenografts in immunodeficient mice with CuB at either low (0.5 mg/kg) or high (1 mg/kg) doses in combination with either DOC (20 mg/kg) or GEM (12.5mg/kg) significantly reduced tumor volume as compared with monotherapy of each drug. Importantly, no significant toxicity was noted with low-dose CuB in combination with either DOC or GEM. In conclusion, combination of CuB at a relatively low concentration with either of the chemotherapeutic agents, DOC or GEM, shows prominent antiproliferative activity against breast cancer cells without increased toxicity. This promising combination should be examined in therapeutic trials of breast cancer.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/pathology , Triterpenes/pharmacology , Animals , Antineoplastic Agents, Phytogenic/toxicity , Apoptosis/drug effects , Bone Marrow Cells/drug effects , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Docetaxel , Drug Synergism , Female , Humans , Mice , Taxoids/pharmacology , Triterpenes/toxicity , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.
