UK: Floxacin antibiotics may enhance the treatment of patients with lung and bladder Cancer, finds a new study.The findings of this study were published in Science Translational Medicine.
Due to the development of drug-resistant metastases, lung and bladder malignancies are difficult to treat.
In both in vitro and in vivo models, Chrysostomou et al. revealed that the p90 ribosomal protein S6 kinase 4 (RSK4) is implicated in the development of drug resistance and metastatic invasion. As a result, better treatments that address these two mechanisms are desperately needed to enhance clinical outcomes.
RSK4 has been discovered as a driver of treatment resistance and metastasis in lung and bladder cancer cells by researchers. In a tail vein injection model, silencing this kinase by RNA interference or CRISPR sensitized tumor cells to chemotherapy and inhibited metastasis in vitro and in vivo.
Several floxacin antibiotics were identified as effective RSK4 activation inhibitors in drug screening, and trovafloxacin replicated all effects of RSK4 silencing in vitro and in/ex vivo utilizing lung cancer xenograft and genetically modified mice models, as well as bladder tumor explants. Researchers identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation by binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif using x-ray structure determination and Markov transient and Deuterium exchange analyses.
Finally, in the big placebo-controlled randomized phase 3 SIGNIFICANT study, patients undergoing chemotherapy and taking preventive levofloxacin had considerably longer long-term overall survival durations. As a result, RSK4 inhibition may be a viable therapeutic approach for treating lung and bladder cancer. This research, along with the discovery that levofloxacin increased patient survival in a big clinical study, shows that floxacins may be repurposed against lung and bladder malignancies just as RSK4.
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Chrysostomou S, Roy R, Prischi F, Thamlikitkul L, Chapman KL, Mufti U, Peach R, Ding L, Hancock D, Moore C, Molina-Arcas M, Mauri F, Pinato DJ, Abrahams JM, Ottaviani S, Castellano L, Giamas G, Pascoe J, Moonamale D, Pirrie S, Gaunt C, Billingham L, Steven NM, Cullen M, Hrouda D, Winkler M, Post J, Cohen P, Salpeter SJ, Bar V, Zundelevich A, Golan S, Leibovici D, Lara R, Klug DR, Yaliraki SN, Barahona M, Wang Y, Downward J, Skehel JM, Ali MMU, Seckl MJ, Pardo OE. Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Sci Transl Med. 2021 Jul 14;13(602):eaba4627. doi: 10.1126/scitranslmed.aba4627. PMID: 34261798; PMCID: PMC7611705.