title: Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer.
abstract: Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells.
authors.affiliation: Galactophore Department, JingZhou Central Hospital, JingZhou, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Forensic Surgery Department, JingZhou Traditional Chinese Medicine Hospital, JingZhou, People's Republic of China. Electronic address: liruishu2016@yahoo.com.
authors.forename: Ruishu
authors.initials: R
authors.lastname: Li
authors.affiliation: Endocrinology Department, JingZhou Central Hospital, JingZhou, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D058492:Drug Repositioning; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D064704:Levofloxacin / Q000494:pharmacology* / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects*; D001678:Organelle Biogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D005472:Fluorouracil; D064704:Levofloxacin; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Breast cancer; Levofloxacin; MAPK/ERK; Mitochondrial biogenesis; PI3K/Akt/mTOR