Repurposing of niclosamide as a STAT3 inhibitor to enhance the anticancer effect of chemotherapeutic drugs in treating colorectal cancer.

Abstract

AIMS:

Colorectal cancer (CRC) is the third most common cancer worldwide. Mutation of various cell signaling molecules or aberrant activation of signaling pathways leads to poor response to chemotherapy in CRC. Signal transducer and activator of transcription protein 3 (STAT3) is an important signaling molecule, which plays crucial roles in regulating cell survival and growth. In this study, the potentitation of chemotherapy by putative STAT3 inhibitors for treating CRC was investigated.

MAIN METHODS:

A few putative STAT3 inhibitors were investigated. Niclosamide, originally indicated for the treatment of tapeworm infection, was chosen for further investigation in five CRC cell lines (HCT116, HT29, HCC2998, LoVo and SW480). Western blot analysis was used to evaluate the expression of STAT3/phospho-STAT3 and its downstream targets. Sulforhodamine B assay was used to evaluate the cytotoxicity of drug combinations. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect.

KEY FINDINGS:

Niclosamide was found to inhibit expression and activation of STAT3 in a concentration- and time-dependent manner, thereby downregulating STAT3 downstream targets including survivin and cyclin-D1 to induce apoptosis and cell cycle arrest. When combined with niclosamide or specific STAT3 inhibitor (C188-9), the cytotoxicity and DNA damage response from SN38 (the active metabolite from irinotecan) were significantly enhanced. The sequential exposure of SN38 followed by niclosamide was found to be the most potent treatment sequence for the drug combination.

SIGNIFICANCE:

Niclosamide represents a promising candidate for repurposing to potentiate the anticancer activity of chemotherapeutic drugs.

• Authors: Mia M Wu, Z Zhang, Christy W S Tong, ViVi W Yan, William C S Cho, Kenneth K W To
• Journal: Life sciences (Life Sci) Vol. 262 Pg. 118522 (Dec 01 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33011217 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• Irinotecan
• Niclosamide

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Repositioning
• Drug Synergism
• HCT116 Cells
• HT29 Cells
• Humans
• Irinotecan (administration & dosage, pharmacology)
• Niclosamide (administration & dosage, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Time Factors