Modulation of cancer signalling pathway(s) in two -stage mouse skin tumorigenesis by annonacin
Abstract 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 inve...
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| Format: | Article |
| Language: | English |
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BMC
2019-09-01
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| Series: | BMC Complementary and Alternative Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12906-019-2650-1 |
| _version_ | 1818316874831626240 |
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| author | Mohd Rohaizad Md Roduan Roslida Abd Hamid Norhafizah Mohtarrudin |
| author_facet | Mohd Rohaizad Md Roduan Roslida Abd Hamid Norhafizah Mohtarrudin |
| author_sort | Mohd Rohaizad Md Roduan |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T09:28:22Z |
| format | Article |
| id | doaj.art-a243c649c66b4bafba1bc32ac0f9232c |
| institution | Directory Open Access Journal |
| issn | 1472-6882 |
| language | English |
| last_indexed | 2024-12-13T09:28:22Z |
| publishDate | 2019-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Complementary and Alternative Medicine |
| spelling | doaj.art-a243c649c66b4bafba1bc32ac0f9232c2022-12-21T23:52:34ZengBMCBMC Complementary and Alternative Medicine1472-68822019-09-0119111610.1186/s12906-019-2650-1Modulation of cancer signalling pathway(s) in two -stage mouse skin tumorigenesis by annonacinMohd Rohaizad Md Roduan0Roslida Abd Hamid1Norhafizah Mohtarrudin2Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra MalaysiaDepartment of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra MalaysiaDepartment of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra MalaysiaAbstract 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.http://link.springer.com/article/10.1186/s12906-019-2650-1AnnonacinAntitumor promotionGene expressionSkin tumorigenesis |
| spellingShingle | Mohd Rohaizad Md Roduan Roslida Abd Hamid Norhafizah Mohtarrudin Modulation of cancer signalling pathway(s) in two -stage mouse skin tumorigenesis by annonacin BMC Complementary and Alternative Medicine Annonacin Antitumor promotion Gene expression Skin tumorigenesis |
| title | 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_short | 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 |
| topic | Annonacin Antitumor promotion Gene expression Skin tumorigenesis |
| url | http://link.springer.com/article/10.1186/s12906-019-2650-1 |
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