Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN to overcome drug and radiation resistance.
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http://dx.doi.org/10.1016/j.canlet.2021.03.026 | DOI Listing |
Sci Rep
December 2024
Department of Clinical Pharmacy, Baoshan Hospital Affiliated to, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
This study investigates the potential treatment of breast cancer utilizing Gentiana robusta King ex Hook. f. (QJ) through an integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulation.
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December 2024
Department of Breast Surgery, Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, China.
Early prediction of patient responses to neoadjuvant chemotherapy (NACT) is essential for the precision treatment of early breast cancer (EBC). Therefore, this study aims to noninvasively and early predict pathological complete response (pCR). We used dynamic ultrasound (US) imaging changes acquired during NACT, along with clinicopathological features, to create a nomogram and construct a machine learning model.
View Article and Find Full Text PDFMetaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane.
View Article and Find Full Text PDFthe evolution of axillary management in breast cancer has witnessed significant changes in recent decades, leading to an overall reduction in surgical interventions. There have been notable shifts in practice, aiming to minimize morbidity while maintaining oncologic outcomes and accurate staging for newly diagnosed breast cancer patients. These advancements have been facilitated by the improved efficacy of adjuvant therapies.
View Article and Find Full Text PDFthe axillary reverse mapping (ARM) procedure aims to preserve the lymphatic drainage structures of the upper extremity during axillary surgery for breast cancer, thereby reducing the risk of lymphedema in the upper limb. Material and this prospective study included 57 patients with breast cancer who underwent SLNB and ARM. The sentinel lymph node (SLN) was identified using a radioactive tracer.
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