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Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin

Background: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate...

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Main Authors: Md Roduan, Mohd Rohaizad, Abd Hamid @ Abdul Razak, Roslida, Mohtarrudin, Norhafizah
Format: Article
Language:English
Published: BioMed Central 2019
Online Access:http://psasir.upm.edu.my/id/eprint/81400/1/Modulation%20of%20cancer%20signalling%20pathway%28s%29%20in%20two-stage%20mouse%20skin%20tumorigenesis%20by%20annonacin.pdf
http://psasir.upm.edu.my/id/eprint/81400/
https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-019-2650-1
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spelling my.upm.eprints.814002021-01-31T17:40:06Z http://psasir.upm.edu.my/id/eprint/81400/ Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin Md Roduan, Mohd Rohaizad Abd Hamid @ Abdul Razak, Roslida Mohtarrudin, Norhafizah Background: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. Methods: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin. Results: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. Conclusions: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity. BioMed Central 2019 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/81400/1/Modulation%20of%20cancer%20signalling%20pathway%28s%29%20in%20two-stage%20mouse%20skin%20tumorigenesis%20by%20annonacin.pdf Md Roduan, Mohd Rohaizad and Abd Hamid @ Abdul Razak, Roslida and Mohtarrudin, Norhafizah (2019) Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin. BMC Complementary and Alternative Medicine, 19 (238). pp. 1-16. ISSN 1472-6882 https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-019-2650-1 10.1186/s12906-019-2650-1
institution Universiti Putra Malaysia
building UPM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Putra Malaysia
content_source UPM Institutional Repository
url_provider http://psasir.upm.edu.my/
language English
description Background: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. Methods: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin. Results: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. Conclusions: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.
format Article
author Md Roduan, Mohd Rohaizad
Abd Hamid @ Abdul Razak, Roslida
Mohtarrudin, Norhafizah
spellingShingle Md Roduan, Mohd Rohaizad
Abd Hamid @ Abdul Razak, Roslida
Mohtarrudin, Norhafizah
Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
author_facet Md Roduan, Mohd Rohaizad
Abd Hamid @ Abdul Razak, Roslida
Mohtarrudin, Norhafizah
author_sort Md Roduan, Mohd Rohaizad
title Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
title_short Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
title_full Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
title_fullStr Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
title_full_unstemmed Modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
title_sort modulation of cancer signalling pathway(s) in two-stage mouse skin tumorigenesis by annonacin
publisher BioMed Central
publishDate 2019
url http://psasir.upm.edu.my/id/eprint/81400/1/Modulation%20of%20cancer%20signalling%20pathway%28s%29%20in%20two-stage%20mouse%20skin%20tumorigenesis%20by%20annonacin.pdf
http://psasir.upm.edu.my/id/eprint/81400/
https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-019-2650-1
_version_ 1691734454163210240
score 13.211869

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