Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer

Journal Article · Fri Mar 18 04:00:00 EDT 2016 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2016.02.072· OSTI ID:22596302

Yu, Min ^[1]; Li, Ruishu ^[2]; Zhang, Juan ^[3]

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1. Galactophore Department, JingZhou Central Hospital, JingZhou (China)
2. Forensic Surgery Department, JingZhou Traditional Chinese Medicine Hospital, JingZhou (China)
3. Endocrinology Department, JingZhou Central Hospital, JingZhou (China)

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. - Highlights: • Levofloxacin targets a panel of breast cancer cell lines in vitro and in vivo. • Levofloxacin acts synergistically with 5-Fluorouracil in breast cancer. • Levofloxacin targets breast cancer cells via inhibiting mitochondrial biogenesis. • Breast cancer cells have increased mitochondrial biogenesis than normal cells. • Mitochondrial biogenesis inhibition lead to deactivation of PI3K/Akt/mTOR pathway.

• OSTI ID: 22596302
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 471; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBIOTICS
APOPTOSIS
ATP
CARNITINE
CELL PROLIFERATION
DEACTIVATION
IN VITRO
IN VIVO
INHIBITION
MAMMARY GLANDS
MEMBRANES
MICE
MITOCHONDRIA
NEOPLASMS
RESPIRATION
SENSITIVITY
URACILS