1,3-bis(3,5-dichlorophenyl) Urea Compound ‘COH-SR4’ Inhibits Proliferation and Activates Apoptosis in Melanoma
Open accessAbstract
The current clinical interventions in malignant melanomas are met with poor response to therapy due to dynamic regulation of multiple melanoma signaling pathways consequent to administration of single target agents. In this context of limited response to single target agents, novel candidate molecules capable of effectively inducing tumor inhibition along with targeting multiple critical nodes of melanoma signaling assume translational significance. In this regard, we investigated the anti-cancer effects of a novel dichlorophenyl urea compound called COH-SR4 in melanoma. The SR4 treatment decreased the survival and inhibited the clonogenic potential of melanomas along with inducing apoptosis in vitro cultures. SR4 treatments lead to inhibition of GST activity along with causing G2/M phase cell cycle arrest. Oral administration of 4 mg/kg SR4 leads to effective inhibition of tumor burdens in both syngeneic and nude mouse models of melanoma. The SR4 treatment was well tolerated and no overt toxicity was observed. The histopathological examination of resected tumor sections revealed decreased blood vessels, decrease in the levels of angiogenesis marker, CD31, and proliferation marker, Ki67, along with an increase in pAMPK levels. Western blot analyses of resected tumor lysates revealed increased PARP cleavage, Bim, pAMPK along with decreased pAkt, vimentin, fibronectin, CDK4 and cyclin B1. Thus, SR4 represents a novel candidate for the further development of mono and combinatorial therapies to effectively target aggressive and therapeutically refractory melanomas.
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The best-known effect of mitochondrial uncouplers is a drop in ATP/AMP levels, which induces activation of the AMPK signaling pathway.
“In terms of cell signaling, the best-known effect of mitochondrial uncouplers is probably a drop in ATP/AMP levels, which induces the activation of the AMPK signaling pathway (Figure 1).”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [255]
The effect of mitochondrial uncouplers on ATP/AMP levels and AMPK activation has been found in multiple models and species, including white adipocytes, skeletal muscle cells, cancer cells, and neurons.
“This effect has been found in multiple models and species, including white adipocytes [91,251], skeletal muscle cells [252,253], cancer cells [54,254,255,256], and neurons [257].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [255]
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- Authors
- Singhal, S. S., Figarola, J., Singhal, J., Leake, K., Nagaprashantha, L., Lincoln, C., Gabriel Gugiu, B., Horne, D., Jove, R., Awasthi, S., & Rahbar, S.
- Affiliations
- City Of Hope National Medical Center (US)
- Corresponding author
- Singhal, Sharad S.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 84
- Issue
- 11
- Pages
- 1419-1427
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC3747778
- OpenAlex
- W1983755598
- Cited by
- 20
- References
- 51
- Citations by year
- 2025: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 3 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 1 · 2013: 6
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- USPHS (CA 77495, CA 115674)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- melanoma, apoptosis, cell proliferation inhibition, G2/M cell cycle arrest, AMPK activation, angiogenesis, tumor growth inhibition, combination therapy, CDK4, cyclin B1, Ki-67, CD31
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Melanoma, Mice, Inbred C57BL, Mice, Nude, Phenylurea Compounds, Mass Spectrometry, Blotting, Western, Apoptosis, In Situ Nick-End Labeling, Cell Proliferation, Mice
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