Floxacin antibiotics may enhance the treatment of patients with lung and bladder cancer, according to research published in Science Translational Medicine.
Preclinical research showed that floxacin antibiotics inhibit the protein kinase RSK4, thereby sensitizing lung and bladder cancer cells to chemotherapy and hindering metastasis.
Clinical research showed that cancer patients receiving chemotherapy had longer overall survival (OS) when they also received treatment with levofloxacin.
The researchers first found that RSK4 regulates chemosensitivity and controls the migration and invasion of lung and bladder cancer cells. Inhibiting RSK4 via CRISPR or RNA interference sensitized cancer cells to chemotherapy and prevented metastasis in mice.
A drug screen showed that floxacin antibiotics can inhibit RSK4. Subsequent experiments showed that trovafloxacin can sensitize cancer cells to chemotherapy and inhibit tumor growth in vivo and ex vivo.
Analyses of patient samples showed that RSK4 mRNA is overexpressed in patients with lung or bladder cancer. In addition, lung cancer survival data showed that high RSK4 mRNA expression was associated with poorer prognosis.
An analysis of data from the phase 3 SIGNIFICANT trial (ClinicalTrials.gov Identifier: NCT00005590) suggested that levofloxacin can prolong OS in patients with advanced cancers receiving chemotherapy.
The median OS was 72 months among patients who received levofloxacin and 59 months among patients who received placebo (hazard ratio, 0.83; 95% CI, 0.69-0.99; P =.048).
“Sensitivity analysis showed that excluding patients who died during treatment did not change the conclusions, and thus, this improvement in OS could not be due to a reduction in infective deaths because of the antibacterial effect of levofloxacin,” the researchers noted.
“Collectively, our data suggest that RSK4-targeting floxacins such as levofloxacin could be repurposed for proof-of-concept combination studies with existing chemotherapeutics in patients with lung and bladder cancer,” the researchers concluded.
Disclosures: This research was supported by the Cancer Research UK Imperial Centre and others. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Chrysostomou S, Roy R, Prischi F, et al. Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Sci Transl Med. 2021;13(602):eaba4627. doi:10.1126/scitranslmed.aba4627