A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death

Sheema Khan, Renu Chib, Bhahwal A. Shah, Z. A. Wani, Niha Dhar, Dilip M. Mondhe, Surrinder Lattoo, S. K. Jain, Subhash C. Taneja, Jaswant Singh

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90% of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48% at 30 mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalEuropean Journal of Pharmacology
Volume660
Issue number2-3
DOIs
StatePublished - Jun 25 2011

Fingerprint

Human papillomavirus 18
Telomerase
HeLa Cells
Uterine Cervical Neoplasms
Caspase 8
DNA Fragmentation
Caspases
Ascites
Proteolysis
DNA Damage
Neoplasms
Cell Survival
B-Lymphocytes
Western Blotting
Carcinoma
Messenger RNA
boswellic acid
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death. / Khan, Sheema; Chib, Renu; Shah, Bhahwal A.; Wani, Z. A.; Dhar, Niha; Mondhe, Dilip M.; Lattoo, Surrinder; Jain, S. K.; Taneja, Subhash C.; Singh, Jaswant.

In: European Journal of Pharmacology, Vol. 660, No. 2-3, 25.06.2011, p. 241-248.

Research output: Contribution to journalArticle

Khan, Sheema ; Chib, Renu ; Shah, Bhahwal A. ; Wani, Z. A. ; Dhar, Niha ; Mondhe, Dilip M. ; Lattoo, Surrinder ; Jain, S. K. ; Taneja, Subhash C. ; Singh, Jaswant. / A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death. In: European Journal of Pharmacology. 2011 ; Vol. 660, No. 2-3. pp. 241-248.
@article{d659eda6a6154c32850e39d5c8472f85,
title = "A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death",
abstract = "The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90{\%} of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48{\%} at 30 mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.",
author = "Sheema Khan and Renu Chib and Shah, {Bhahwal A.} and Wani, {Z. A.} and Niha Dhar and Mondhe, {Dilip M.} and Surrinder Lattoo and Jain, {S. K.} and Taneja, {Subhash C.} and Jaswant Singh",
year = "2011",
month = "6",
day = "25",
doi = "10.1016/j.ejphar.2011.03.013",
language = "English (US)",
volume = "660",
pages = "241--248",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "2-3",

}

TY - JOUR

T1 - A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death

AU - Khan, Sheema

AU - Chib, Renu

AU - Shah, Bhahwal A.

AU - Wani, Z. A.

AU - Dhar, Niha

AU - Mondhe, Dilip M.

AU - Lattoo, Surrinder

AU - Jain, S. K.

AU - Taneja, Subhash C.

AU - Singh, Jaswant

PY - 2011/6/25

Y1 - 2011/6/25

N2 - The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90% of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48% at 30 mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.

AB - The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in over 90% of cervical cancers. HPV E6 protein promotes the degradation of p53 thereby inhibiting its stabilization and activation. This study demonstrates that treatment with a novel cyano derivative of 11-keto-β-boswellic acid, i.e. butyl 2-cyano-3, 11-dioxours-1,12-dien-24-oate (BCDD) reduced the viral E6 mRNA expression and lead to the accumulation of transcriptionally active p53 in the nucleus of HPV18 HeLa cells following DNA damage. Western blot analysis showed that BCDD robustly up regulated time-dependent expression of p53/PUMA/p21 whereas it deprived cells essentially of p-AKT and NF-κB cell survival signalling cascade. BCDD appeared to gear up PUMA activation through p53 pathway and that both p53 and p21 translocated heavily into the nucleus. Simultaneously, it inhibited anti-apoptotic Bcl-2, augumented Drp-1 expression, disrupted mitochondrial functions causing the activation of proapoptotic proteins and caspases activation. Additionally, BCDD inhibited telomerase expression that's likely to result in a marked reduction of the tumorigenic potential of high-grade cervical cancers. Consequently BCDD caused apoptotic death in cervical cancer cells as evidenced by DNA fragmentation and PARP-cleavage. Further, BCDD did not affect the extrinsic signalling transduction pathway as depicted by its null effect on caspase-8. The in vivo anticancer activity of BCDD was investigated in Ehrlich Ascites carcinoma model where it exhibited tumor regression by 48% at 30 mg/kg, i.p., in mice. These findings indicated that BCDD is a potential candidate that may be found useful in the management of cervical cancer.

UR - http://www.scopus.com/inward/record.url?scp=79956132773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956132773&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2011.03.013

DO - 10.1016/j.ejphar.2011.03.013

M3 - Article

VL - 660

SP - 241

EP - 248

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2-3

ER -