Novel compound 1,3-bis (3,5-dichlorophenyl) urea inhibits lung cancer progression

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Lung cancer management is hindered by p53 mutations and oxidant-stress adaptations in the mercapturic acid pathway (MAP), leading to therapeutic resistance.
• Understanding these mechanisms is crucial for developing effective anti-cancer strategies.

Purpose of the Study:

• To investigate the anti-cancer effects and mechanisms of action of a novel compound, 1,3-bis(3,5-dichlorophenyl) urea (COH-SR4), in lung cancer.
• To evaluate COH-SR4's potential as a therapeutic agent for aggressive and drug-resistant lung tumors.

Main Methods:

• In vitro studies involved treating lung cancer cells with COH-SR4 to assess survival, clonogenic potential, apoptosis, GST activity, cell cycle progression, and protein expression.
• In vivo studies utilized H358 lung cancer xenografts in mice, evaluating tumor regression, toxicity, and analyzing tumor tissues for molecular markers (pAMPK, Ki67, CD31, pAkt, Bcl2, Bax, cleaved PARP, vimentin, E-cadherin).
• AMP-activated protein kinase (AMPK) pathway activation and its role were investigated using knock-down experiments.

Main Results:

• COH-SR4 significantly inhibited lung cancer cell survival, clonogenic potential, and induced apoptosis.
• The compound caused G0/G1 cell cycle arrest, inhibited GST activity, and modulated cell cycle regulatory proteins.
• COH-SR4 activated the AMPK pathway, leading to tumor regression in vivo with no overt toxicity, and altered key molecular markers associated with proliferation, apoptosis, and epithelial-mesenchymal transition.

Conclusions:

• COH-SR4 demonstrates potent anti-cancer activity against lung cancer cells in vitro and in vivo.
• Activation of the AMPK pathway is a key mechanism underlying COH-SR4's efficacy.
• COH-SR4 represents a promising novel therapeutic candidate for targeting aggressive and drug-resistant lung tumors.