Repurposing of niclosamide (a putative STAT3 inhibitor) to potentiate chemotherapeutic drugs in treating colorectal cancer
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AbstractBackground: Chemotherapy remains the first-line treatment option for colorectal cancer (CRC) patients. However, aberrant cell signaling regulation leads to poor drug response. Signal transducer and activator of transcription protein 3 (STAT3) is an important signaling molecule driving cancer cell survival. Its overexpression is associated with poor prognosis in CRC patients. This study aimed to repurpose approved drugs with putative STAT3 inhibitory effect to potentiate chemotherapeutic drugs for CRC treatment.

Methods: The combinations of four putative STAT3 inhibitors (niclosamide, nifuroxazide, C118-9, SH-4-54) and three chemotherapeutic drugs (5-fluorouracil, SN38 and oxaliplatin) were evaluated in five human CRC cell lines harboring different genetic abnormalities (HCT116, HT29, HCC2998, LoVo, SW480). Antiproliferative effect was assessed by the sulforhodamine B assay. Median effect analysis was performed to identify the synergistic drug combinations. Flow cytometric assays were used to detect apoptosis and cell cycle regulation. Inhibition of STAT3 and its downstream targets were examined by Western blot analysis. The effect of drug combinations on DNA damage was also investigated.

Results: The combination of SN38 and niclosamide was found to be the most synergistic in multiple CRC cell lines. Interestingly, sequential treatment with SN38 preceding niclosamide gave rise to more synergistic antiproliferative and apoptotic effect. The combination was also shown to produce the most remarkable enhancement in G2/M cell cycle arrest. Compared with individual treatment alone, the SN38-niclosamide combination was shown to cause more remarkable STAT3 inhibition and down-regulation of the cell cycle regulators Cyclin-D1 and Cyclin-B. Moreover, niclosamide was also found to prevent SN38-induced STAT3 up-regulation and enhance DNA damage.

Conclusion: Niclosamide may be repurposed to potentiate chemotherapeutic drugs for treating CRC. The beneficial combinations were found to be schedule-dependent, as exemplified by the most synergistic effect from SN38-preceding-niclosamide combination. STAT3 inhibition and enhanced induction of DNA damage in cancer cells contribute to the efficacious combination.
Acceptance Date03/11/2019
All Author(s) ListMia Mingxia WU, Christy Wing Sum TONG, Vivi Wei YAN, Kenneth Kin-Wah TO
Name of Conference2019 National Cancer Research Institute (NCRI) Cancer Conference
Start Date of Conference03/11/2019
End Date of Conference05/11/2019
Place of ConferenceGlasgow, UK
Country/Region of ConferenceGreat Britain
Year2019
LanguagesEnglish-United Kingdom

Last updated on 2020-02-06 at 11:53