Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport

Raghavendra Gowda, Gajanan S. Inamdar, Omer Kuzu, Saketh S. Dinavahi, Jacek Krzeminski, Madhu Babu Battu, Sreedhara R. Voleti, Shantu Amin, Gavin Robertson

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)28260-28277
Number of pages18
JournalOncotarget
Volume8
Issue number17
DOIs
StatePublished - Jan 1 2017

Fingerprint

Structure-Activity Relationship
Cholesterol
Lysosomes
Neoplasms
Computer Simulation
Antineoplastic Agents
Melanoma
Cell Death
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Gowda, Raghavendra ; Inamdar, Gajanan S. ; Kuzu, Omer ; Dinavahi, Saketh S. ; Krzeminski, Jacek ; Battu, Madhu Babu ; Voleti, Sreedhara R. ; Amin, Shantu ; Robertson, Gavin. / Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport. In: Oncotarget. 2017 ; Vol. 8, No. 17. pp. 28260-28277.
@article{889a94d37c4c4f5c9aa7e62c64508d7d,
title = "Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport",
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.",
author = "Raghavendra Gowda and Inamdar, {Gajanan S.} and Omer Kuzu and Dinavahi, {Saketh S.} and Jacek Krzeminski and Battu, {Madhu Babu} and Voleti, {Sreedhara R.} and Shantu Amin and Gavin Robertson",
year = "2017",
month = "1",
day = "1",
doi = "10.18632/oncotarget.16002",
language = "English (US)",
volume = "8",
pages = "28260--28277",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "17",

}

Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport. / Gowda, Raghavendra; Inamdar, Gajanan S.; Kuzu, Omer; Dinavahi, Saketh S.; Krzeminski, Jacek; Battu, Madhu Babu; Voleti, Sreedhara R.; Amin, Shantu; Robertson, Gavin.

In: Oncotarget, Vol. 8, No. 17, 01.01.2017, p. 28260-28277.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport

AU - Gowda, Raghavendra

AU - Inamdar, Gajanan S.

AU - Kuzu, Omer

AU - Dinavahi, Saketh S.

AU - Krzeminski, Jacek

AU - Battu, Madhu Babu

AU - Voleti, Sreedhara R.

AU - Amin, Shantu

AU - Robertson, Gavin

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85018397039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018397039&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.16002

DO - 10.18632/oncotarget.16002

M3 - Article

C2 - 28423677

AN - SCOPUS:85018397039

VL - 8

SP - 28260

EP - 28277

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 17

ER -