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Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation.

ABSTRACT: In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.

SUBMITTER: Salerno L

PROVIDER: S-EPMC8231349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHeme oxygenase 1 (HO-1) has been reported to be very important in the pathogenesis or progression of multiple types of cancer. Identification of novel hmox1 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways, and possible treatment targets.MethodsImmunoprecipitation and mass spectrometry analyses were used to identify novel regulators of HO-1. The association of the 14-3-3ζ protein with HO-1 and modulation of the stability of HO-1 were investigated by co-immunoprecipitation, immunofluorescence, western blotting, and quantitative RT-PCR. Degradation and in vivo ubiquitination assays were utilized to examine whether 14-3-3ζ stabilizes the HO-1 protein by inhibiting its ubiquitination. The effect of 14-3-3ζ on proliferation was investigated by function assays conducted in vitro using the CCK-8 and colony formation assays and in vivo in a xenograft mouse model. The biological functions of the 14-3-3ζ/HO-1 axis were demonstrated by western blotting and rescue experiments. Using gain-of-function and loss-of-function strategies, we further clarified the impact of 14-3-3ζ/HO-1 complex on the signal transducers and activators of transcription 3 (STAT3) signaling pathway in cancer cells.ResultsWe identified 14-3-3ζ as a novel HO-1 binding protein. The binding inhibited the ubiquitination and proteasome-mediated degradation of HO-1, thus facilitating its stabilization. Enforced expression of 14-3-3ζ significantly promoted cell proliferation in vitro, as well as tumorigenesis in vivo, while 14-3-3ζ knockdown had opposite effects. The data indicated that 14-3-3ζ can stabilize HO-1 expression and thus influence cancer cell proliferation. We further demonstrated the involvement of the STAT3 pathway in 14-3-3ζ/HO-1 regulation of hepatocellular carcinoma cell proliferation.ConclusionsCollectively, these data show that 14-3-3ζ regulates the stability of HO-1 to promote cancer cell proliferation and STAT3 signaling activation. The data establish the 14-3-3ζ-HO-1-STAT3 axis as an important regulatory mechanism of cancer cell growth and implicate HO-1 and 14-3-3ζ as potential therapeutic targets in hepatocellular carcinoma.

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Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation.

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