Dataset Information

Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases.

ABSTRACT: Triple negative breast cancer (TNBC) patients have a high risk of brain metastases. This deadly disease represents a major challenge for successful treatment, in part because of the poor ability of drugs to penetrate the blood-brain barrier. Antipsychotic drugs show good bioavailability in the brain, and some of them have exhibited anticancer effects in several cancer types. In this study, we investigated the potential of repurposing fluphenazine hydrochloride (Flu) for the treatment of TNBC and the brain metastases. Our data showed that Flu inhibited survival of metastatic TNBC cells. It induced G0/G1 cell cycle arrest and promoted mitochondria-mediated intrinsic apoptosis in vitro. Pharmacokinetic studies in BALB/c mice showed a brain/plasma drug concentration ratio of Flu above 25 for at least 24 hours after dosing. Flu moderately suppressed tumor growth in a TNBC subcutaneous xenograft mouse model. Importantly, Flu exhibited good anti-metastatic potential in a mouse brain metastasis model with an inhibition rate of 85%. In addition, Flu showed a strong inhibitory effect on spontaneous lung metastasis. Moreover, Flu didn't cause serious side effects in the mice. Taken together, this study prompts further preclinical and clinical investigation into repurposing Flu for treating metastatic TNBC patients, which urgently need new treatment options.

SUBMITTER: Xu F

PROVIDER: S-EPMC6448056 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases.

Xu Fuyan F Xia Yong Y Feng Zhanzhan Z Lin Wentao W Xue Qiang Q Jiang Jinrui J Yu Xi X Peng Cuiting C Luo Min M Yang Yufei Y Wei Yuquan Y Yu Luoting L

American journal of cancer research 20190301 3

Triple negative breast cancer (TNBC) patients have a high risk of brain metastases. This deadly disease represents a major challenge for successful treatment, in part because of the poor ability of drugs to penetrate the blood-brain barrier. Antipsychotic drugs show good bioavailability in the brain, and some of them have exhibited anticancer effects in several cancer types. In this study, we investigated the potential of repurposing fluphenazine hydrochloride (Flu) for the treatment of TNBC and ...[more]

PMID: 30949404

Similar Datasets

Project description:Lung metastasis is the major cause of death in patients with triple negative breast cancer (TNBC), an aggressive subtype of breast cancer with no effective therapy at present. It has been proposed that dual-targeted therapy, ie, targeting chemotherapeutic agents to both tumor vasculature and cancer cells, may offer some advantages. The present work was aimed to develop a dual-targeted synergistic drug combination nanomedicine for the treatment of lung metastases of TNBC. Thus, Arg-Gly-Asp peptide (RGD)-conjugated, doxorubicin (DOX) and mitomycin C (MMC) co-loaded polymer-lipid hybrid nanoparticles (RGD-DMPLN) were prepared and characterized. The synergism between DOX and MMC and the effect of RGD-DMPLN on cell morphology and cell viability were evaluated in human MDA-MB-231 cells in vitro. The optimal RGD density on nanoparticles (NPs) was identified based on the biodistribution and tumor accumulation of the NPs in a murine lung metastatic model of MDA-MB-231 cells. The microscopic distribution of RGD-conjugated NPs in lung metastases was examined using confocal microscopy. The anticancer efficacy of RGD-DMPLN was investigated in the lung metastatic model. A synergistic ratio of DOX and MMC was found in the MDA-MB-231 human TNBC cells. RGD-DMPLN induced morphological changes and enhanced cytotoxicity in vitro. NPs with a median RGD density showed the highest accumulation in lung metastases by targeting both tumor vasculature and cancer cells. Compared to free drugs, RGD-DMPLN exhibited significantly low toxicity to the host, liver and heart. Compared to non-targeted DMPLN or free drugs, administration of RGD-DMPLN (10 mg/kg, iv) resulted in a 4.7-fold and 31-fold reduction in the burden of lung metastases measured by bioluminescence imaging, a 2.4-fold and 4.0-fold reduction in the lung metastasis area index, and a 35% and 57% longer median survival time, respectively. Dual-targeted RGD-DMPLN, with optimal RGD density, significantly inhibited the progression of lung metastasis and extended host survival.

Project description:Breast cancer brain metastases (BM) affect younger women disproportionally, including those lacking estrogen receptor (ER), progesterone receptor, and HER2 (known as triple-negative breast cancer; TNBC). Previous studies in preclinical models showed that pre-menopausal levels of estradiol (E2) promote TNBC-BM through incompletely understood mechanisms involving reactive astrocytes. Herein, a novel mechanism involving E2-dependent upregulation of brain-derived neurotrophic factor (BDNF) in astrocytes, and subsequent activation of tumor cell tropomyosin kinase receptor B (TrkB), is identified. E2 increased experimental BM of TNBC 4T1BR5 and E0771 cells by 21 and 3.6 fold, respectively, compared to E2-depleted mice. ERα+ reactive astrocytes were found at early and late stages of BM, and E2 upregulated BDNF in ER+ reactive astrocytes in vitro and in vivo. TrkB was expressed in TNBC brain-trophic cell lines, BM-patient-derived xenografts, and breast cancer BM. Conditioned media from E2-treated astrocytes (CM-E2) activated TrkB and downstream AKT, ERK, and PLC-γ signaling in TNBC cells, increasing their invasiveness and tumor-initiating capability in vitro. The promotion of BM by E2-activated astrocytes was found to be more complex, involving feedback loops and other receptor tyrosine kinases. In 4T1BR5 cells, there was a positive feedback loop whereby astrocytic BDNF induced cancer cell BDNF translation. Upregulation of cancer cell BDNF was required to promote full invasiveness of 4T1BR5 in response to CM-E2, and was observed in brain metastatic cells in E2-treated mice in vivo. Moreover, the non-competitive BDNF/TrkB inhibitor ANA-12 reduced E2-induced 4T1BR5 BM to levels similar to OVX mice. BDNF also activated EGFR in TrkB+EGFR+ TNBC cells, suggesting that E2 action through astrocytes activates redundant pathways promoting BM. These findings have important therapeutic implications, as they provide a rationale to use E2-depletion therapies or TrkB inhibitors to prevent or delay development of BM in younger women.

Dataset Information

Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases.

Publications

Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets