Structure activity relationship of plumbagin in BRCA1 related cancer cells

Thasni Karedath Abdul Azis, T. Ratheeshkumar, G. Rojini, K. C. Sivakumar, Rakesh Sathish Nair, G. Srinivas, Asoke Banerji, Veena Somasundaram, Priya Srinivas

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential-Δψm, suppression subtractive hybridization, microarray, molecular docking and estrogen receptor-DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti-cancer activities were in the order plumbagin>1,4-naphthaquinone>juglone>lawsone>menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL-DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells.

Original languageEnglish
Pages (from-to)392-403
Number of pages12
JournalMolecular Carcinogenesis
Volume52
Issue number5
DOIs
Publication statusPublished - 1 May 2013
Externally publishedYes

Fingerprint

Structure-Activity Relationship
Neoplasms
Apoptosis
Electrophoretic Mobility Shift Assay
Antineoplastic Agents
Ovarian Neoplasms
Electrophoresis
plumbagin
Vitamin K 3
Mitochondrial Membrane Potential
Cell Cycle Checkpoints
Estrogen Receptors
Reactive Oxygen Species
Flow Cytometry
Estrogens
Ligands
DNA

Keywords

  • BRCA1
  • Microarray
  • Plumbagin
  • Quinones
  • Suppression subtractive hybridization

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Karedath Abdul Azis, T., Ratheeshkumar, T., Rojini, G., Sivakumar, K. C., Nair, R. S., Srinivas, G., ... Srinivas, P. (2013). Structure activity relationship of plumbagin in BRCA1 related cancer cells. Molecular Carcinogenesis, 52(5), 392-403. https://doi.org/10.1002/mc.21877

Structure activity relationship of plumbagin in BRCA1 related cancer cells. / Karedath Abdul Azis, Thasni; Ratheeshkumar, T.; Rojini, G.; Sivakumar, K. C.; Nair, Rakesh Sathish; Srinivas, G.; Banerji, Asoke; Somasundaram, Veena; Srinivas, Priya.

In: Molecular Carcinogenesis, Vol. 52, No. 5, 01.05.2013, p. 392-403.

Research output: Contribution to journalArticle

Karedath Abdul Azis, T, Ratheeshkumar, T, Rojini, G, Sivakumar, KC, Nair, RS, Srinivas, G, Banerji, A, Somasundaram, V & Srinivas, P 2013, 'Structure activity relationship of plumbagin in BRCA1 related cancer cells', Molecular Carcinogenesis, vol. 52, no. 5, pp. 392-403. https://doi.org/10.1002/mc.21877
Karedath Abdul Azis, Thasni ; Ratheeshkumar, T. ; Rojini, G. ; Sivakumar, K. C. ; Nair, Rakesh Sathish ; Srinivas, G. ; Banerji, Asoke ; Somasundaram, Veena ; Srinivas, Priya. / Structure activity relationship of plumbagin in BRCA1 related cancer cells. In: Molecular Carcinogenesis. 2013 ; Vol. 52, No. 5. pp. 392-403.
@article{ccb2428235a1450ab52739581b393054,
title = "Structure activity relationship of plumbagin in BRCA1 related cancer cells",
abstract = "It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential-Δψm, suppression subtractive hybridization, microarray, molecular docking and estrogen receptor-DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti-cancer activities were in the order plumbagin>1,4-naphthaquinone>juglone>lawsone>menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL-DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells.",
keywords = "BRCA1, Microarray, Plumbagin, Quinones, Suppression subtractive hybridization",
author = "{Karedath Abdul Azis}, Thasni and T. Ratheeshkumar and G. Rojini and Sivakumar, {K. C.} and Nair, {Rakesh Sathish} and G. Srinivas and Asoke Banerji and Veena Somasundaram and Priya Srinivas",
year = "2013",
month = "5",
day = "1",
doi = "10.1002/mc.21877",
language = "English",
volume = "52",
pages = "392--403",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Structure activity relationship of plumbagin in BRCA1 related cancer cells

AU - Karedath Abdul Azis, Thasni

AU - Ratheeshkumar, T.

AU - Rojini, G.

AU - Sivakumar, K. C.

AU - Nair, Rakesh Sathish

AU - Srinivas, G.

AU - Banerji, Asoke

AU - Somasundaram, Veena

AU - Srinivas, Priya

PY - 2013/5/1

Y1 - 2013/5/1

N2 - It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential-Δψm, suppression subtractive hybridization, microarray, molecular docking and estrogen receptor-DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti-cancer activities were in the order plumbagin>1,4-naphthaquinone>juglone>lawsone>menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL-DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells.

AB - It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential-Δψm, suppression subtractive hybridization, microarray, molecular docking and estrogen receptor-DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti-cancer activities were in the order plumbagin>1,4-naphthaquinone>juglone>lawsone>menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL-DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells.

KW - BRCA1

KW - Microarray

KW - Plumbagin

KW - Quinones

KW - Suppression subtractive hybridization

UR - http://www.scopus.com/inward/record.url?scp=84876104292&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876104292&partnerID=8YFLogxK

U2 - 10.1002/mc.21877

DO - 10.1002/mc.21877

M3 - Article

C2 - 22290577

AN - SCOPUS:84876104292

VL - 52

SP - 392

EP - 403

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 5

ER -