Abstract:
:Melanoma is a highly drug-resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and STAT3 pathways are constitutively activated in 50% to 70% of melanomas, promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK, and STAT3 cascades, a natural product library was screened to identify leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC(50) values of 2 and 9.3 μmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 μmol/L by 40% to 80% and longer exposure increased apoptosis 600%. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK, and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Gowda R,Madhunapantula SV,Kuzu OF,Sharma A,Robertson GPdoi
10.1158/1535-7163.MCT-13-0867subject
Has Abstractpub_date
2014-07-01 00:00:00pages
1679-89issue
7eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-13-0867journal_volume
13pub_type
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