Abstract

Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development.

Highlights

  • Malignant melanoma is the most deadly form of skin cancer due to its high metastatic nature and propensity for developing resistance to chemotherapeutic agents [1]

  • Abietic acid lacks the prominent amino group present on leelamine and does not inhibit cholesterol transport, it was hypothesized that the amino group present in leelamine but absent from abietic acid might confer its anticancer activity [12,13,14]

  • In order to dissect the chemical moiety in leelamine leading to its anticancer activity, derivative compounds of leelamine and abietic acid were synthesized

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Summary

Introduction

Malignant melanoma is the most deadly form of skin cancer due to its high metastatic nature and propensity for developing resistance to chemotherapeutic agents [1]. V600E-BRAF inhibitors, Zelboraf and Tafinlar and a MEK inhibitor Mekinist have been approved by the FDA for treating patients with MAPK pathway activation [2]. These targeted therapeutic approaches are hindered by drug resistance that leads to development of more aggressive recurrent disease [1]. Loss of function mutations in acid sphingomyelinase (ASM) causes type A and B forms of Niemann Pick disease due to impairment of sphingosine efflux from lysosomes, and accumulation of sphingolipid as well as LDL-derived cholesterol in lysosomes [10, 11]

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