Targeting multiple key signaling pathways in melanoma using leelamine

Raghavendra Gowda, Subba Rao V Madhunapantula, Omer F. Kuzu, Arati Sharma, Gavin Robertson

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 IC50 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 mechanismof 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.

Original languageEnglish (US)
Pages (from-to)1679-1689
Number of pages11
JournalMolecular cancer therapeutics
Volume13
Issue number7
DOIs
StatePublished - Jan 1 2014

Fingerprint

Melanoma
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinases
Neoplasms
Cell Proliferation
Apoptosis
Protein Transport
Drug Delivery Systems
Biological Products
Inhibitory Concentration 50
Cultured Cells
Cell Survival
Cholesterol
Body Weight
Growth
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Gowda, Raghavendra ; Madhunapantula, Subba Rao V ; Kuzu, Omer F. ; Sharma, Arati ; Robertson, Gavin. / Targeting multiple key signaling pathways in melanoma using leelamine. In: Molecular cancer therapeutics. 2014 ; Vol. 13, No. 7. pp. 1679-1689.
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Targeting multiple key signaling pathways in melanoma using leelamine. / Gowda, Raghavendra; Madhunapantula, Subba Rao V; Kuzu, Omer F.; Sharma, Arati; Robertson, Gavin.

In: Molecular cancer therapeutics, Vol. 13, No. 7, 01.01.2014, p. 1679-1689.

Research output: Contribution to journalArticle

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