Molecular dissection of anti-colon cancer activity of NARI-29: special focus on H₂O₂ modulated NF-κB and death receptor signaling

Abstract

Accumulating evidence attributes the role of aldose reductase (AR) in modulating ROS and inflammation which are the main factor responsible for cancer progression and drug resistance. Epalrestat is the only AR inhibitor being used in Asian countries. It did not make it to the markets of the USA and Europe due to marginal efficacy as an antioxidant and anti-inflammatory agent owing to difficulty reaching intracellular targets. In our previous studies, we attempted to synthesize the epalrestat analogs and reported that the compound 4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid named as NARI-29 has potent AR inhibition compared to epalrestat. In the current study, we aimed to find the effect of NARI-29 on ROS-induced cancer progression and TRAIL resistance in colon cancer in vitro models. In the first part of the study, we demonstrated that the NARI-29 has specific AKR1B1 inhibition and superior drug-like properties than epalrestat using bioinformatics tools. In the second part of the study, it was proven that NARI-29 has induced the hydrogen peroxide-triggered TRAIL-induced apoptosis in the colon cancer cells via modulating the AKR1B1/4HNE/FOXO3a/DR axis. The selective cytotoxicity of NARI-29 (10-fold) compared to epalrestat (4-fold) toward cancer cells is due to its differential ROS regulation and anti-inflammatory activities. Altogether, these data show that NARI-29 may be a potential candidate for AR inhibitors, which will be used to prevent colon cancer progression and as adjuvant therapy for preventing TRAIL resistance.

HIGHLIGHTS

• AKR1B1 is over-expressed in advanced-stage human colon cancer tissues

• AKR1B1 mediates resistance to H₂O₂ and TRAIL in human CRC cell lines

• A co-activation loop exists between NF-κB and AKR1B1 in CRC cell lines to counteract ROS

• Establishing epalrestat analog, NARI-29 (4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid) as potent anti-colon cancer agents

• NARI-29 induced selective apoptosis in colon cancer cells by differentially modulating the ROS and sensitizing TRAIL

Keywords:

• NARI-29
• AKR1B1
• colorectal carcinoma
• extrinsic apoptosis
• H₂O₂
• ROS

Acknowledgements

The authors would like to acknowledge Dr. USN Murty, Director, National Institute of Pharmaceutical Education and Research Guwahati, for his support throughout the research.

Authors’ contributions

VGMN: conceptualization, investigation, supervision, review & editing. SNP: conceptualization, methodology, visualization, validation, formal analysis, writing original draft. SJ, BR, and GJK: methodology, visualization, formal analysis, and review of draft. JRV: conceptualization and investigation. All authors approved the final version of the manuscript.

Disclosure statement

The authors declare there is no conflict of interest associated with this publication.

Additional information

Funding

The authors are also thankful to the Department of Pharmaceuticals, Ministry of chemicals and fertilizers, Govt. of India for providing funds to carry out the current research work.