Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53

Title:
Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53
Authors:
Liu, Yang; Whelan, Rebecca J. ( 0000-0002-9293-1528 ) ; Pattnaik, Bikash R.; Ludwig, Kai; Subudhi, Enkateswar; Rowland, Helen; Claussen, Nick; Zucker, Noah; Uppal, Shitanshu; Kushner, David M.; Felder, Mildred; Patankar, Manish S.; Kapur, Arvinder
Abstract:
Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE) are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC50 of 1.25 mg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30–40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC50 10 mM (2.3 mg/ml). Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20–40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-a, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53neg SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer.
Citation:
Liu Y., R.J. Whelan, B.R. Pattnaik, K. Ludwig, E. Subudhi, et al. 2012. Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53. PLoS ONE 7(12): e53178.
Publisher:
Public Library of Science
DATE ISSUED:
2012-12-31
Department:
Chemistry and Biochemistry
Type:
Article
PUBLISHED VERSION:
10.1371/journal.pone.0053178
Additional Links:
http://dx.plos.org/10.1371/journal.pone.0053178
PERMANENT LINK:
http://hdl.handle.net/11282/528250

Full metadata record

DC FieldValue Language
dc.contributor.authorLiu, Yangen
dc.contributor.authorWhelan, Rebecca J.en
dc.contributor.authorPattnaik, Bikash R.en
dc.contributor.authorLudwig, Kaien
dc.contributor.authorSubudhi, Enkateswaren
dc.contributor.authorRowland, Helenen
dc.contributor.authorClaussen, Nicken
dc.contributor.authorZucker, Noahen
dc.contributor.authorUppal, Shitanshuen
dc.contributor.authorKushner, David M.en
dc.contributor.authorFelder, Mildreden
dc.contributor.authorPatankar, Manish S.en
dc.contributor.authorKapur, Arvinderen
dc.date.accessioned2015-04-13T13:53:26Zen
dc.date.available2015-04-13T13:53:26Zen
dc.date.issued2012-12-31en
dc.identifier.citationLiu Y., R.J. Whelan, B.R. Pattnaik, K. Ludwig, E. Subudhi, et al. 2012. Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53. PLoS ONE 7(12): e53178.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/11282/528250en
dc.description.abstractNovel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE) are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC50 of 1.25 mg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30–40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC50 10 mM (2.3 mg/ml). Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20–40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-a, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53neg SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.identifier.doi10.1371/journal.pone.0053178en
dc.relation.urlhttp://dx.plos.org/10.1371/journal.pone.0053178en
dc.subject.departmentChemistry and Biochemistryen_US
dc.titleTerpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53en_US
dc.typeArticleen
dc.identifier.journalPLoS ONEen
dc.subject.keywordEndometrial canceren_US
dc.subject.keywordApoptosisen_US
dc.subject.keywordGingeren_US
dc.subject.keywordTerpenoidsen_US
dc.identifier.volume7en_US
dc.identifier.issue12en_US
dc.identifier.startpagee53178en_US
dc.rightsArchived with thanks to PLoS ONEen
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