Novel compound 1,3-bis (3,5-dichlorophenyl) urea inhibits lung cancer progression
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- 作者：Sharad S. Singhal ; James Figarola ; Jyotsana Singhal ; Lokesh Nagaprashantha ; David Berz ; Samuel Rahbar ; Sanjay Awasthi
- 关键词：ACC ; acetyl Co-A carboxylase ; AMPK ; AMP-activated protein kinase ; COH-SR4 ; 1 ; 3-bis (3 ; 5-dichlorophenyl) urea &ldquo ; City of Hope compound&rdquo ; GST ; glutathione S-transferase ; TSC2 ; tuberous sclerosis complex 2 protein
- 刊名：Biochemical Pharmacology
- 出版年：15 December, 2013
- 年：2013
- 卷：86
- 期：12
- 页码：1664-1672
- 全文大小：2221 K
文摘
The successful clinical management of lung cancer is limited by frequent loss-of-function mutations in p53 which cooperates with chronic oxidant-stress induced adaptations in mercapturic acid pathway (MAP) which in turn regulates critical intracellular signaling cascades that determine therapeutic refractoriness. Hence, we investigated the anti-cancer effects and mechanisms of action of a novel compound called 1,3-bis(3,5-dichlorophenyl) urea (COH-SR4) in lung cancer. Treatment with COH-SR4 effectively inhibited the survival and clonogenic potential along with inducing apoptosis in lung cancer cells. COH-SR4 treatment caused the inhibition of GST activity and G0/G1 cell cycle arrest and inhibited the expression of cell cycle regulatory proteins CDK2, CDK4, cyclin A, cyclin B1, cyclin E1, and p27. The COH-SR4 activated AMPK pathway and knock-down of AMPK partially reversed the cytotoxic effects of COH-SR4 in lung cancer. COH-SR4 treatment lead to regression of established xenografts of H358 lung cancer cells without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK, a decrease in the nuclear proliferative marker Ki67 and angiogenesis marker CD31. Western-blot analyses of resected tumor lysates revealed a decrease in pAkt and anti-apoptotic protein Bcl2 along with an increase in pAMPK, pro-apoptotic protein Bax and cleaved PARP levels. Importantly, COH-SR4 lead to decrease in the mesenchymal marker vimentin and increase in the normal epithelial marker E-cadherin. The results from our in-vitro and in-vivo studies reveal that COH-SR4 represents a novel candidate with strong mechanistic relevance to target aggressive and drug-resistant lung tumors.