Synthesis and characterization of a new retinoic acid ECPIRM as potential chemotherapeutic agent for human cutaneous squamous carcinoma
Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers
worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive
and therapeutic agents for a variety of human cancers including CSCC. In this study we
synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and
possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous
carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal
keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2,
CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition
of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid
receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that
ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC.
Keywords: AP-1, cell cycle arrest, cutaneous squamous cell carcinoma, ECPIRM, MAPK, N-(4-ethoxycarbonylphenyl) isoretinamide.
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