Skip to main content
Erschienen in: Tumor Biology 6/2016

12.12.2015 | Original Article

Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer

verfasst von: Sadhna Aggarwal, Satya N. Das

Erschienen in: Tumor Biology | Ausgabe 6/2016

Einloggen, um Zugang zu erhalten

Abstract

Garcinol, a polyisoprenylated benzophenone is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Its ability to inhibit tumour growth has been demonstrated in certain cancers. In this study, we evaluated the potential anti-tumour effects of garcinol on oral squamous cell carcinoma (OSCC) cells. Three OSCC cell lines (SCC-4, SCC-9 and SCC-25) were treated with garcinol for 48 h and its effect on growth and proliferation, clonogenic survival, cell cycle and apoptosis was studied by MTT, clonogenic assay, propidium iodide (PI) staining and annexin-V binding assay, respectively. The alteration in expression of NF-κB and COX-2 was studied by western blot analysis and that of VEGF by ELISA. Garcinol treatment significantly (p < 0.001) inhibited the growth and proliferation and colony formation of OSCC cells with a concomitant induction of apoptosis and cell cycle arrest. It did not show toxic effect on normal cells. It significantly (p < 0.05) reduced the expression of NK-κB and COX-2 expression in treated cells as compared to untreated controls besides inhibiting VEGF expression. It appears that garcinol exerts anti-proliferative, pro-apoptotic, cell-cycle regulatory and anti-angiogenic effects on oral cancer cells through inhibition of NF-κB and COX-2. Thus, garcinol may be developed as a potential chemopreventive and/or chemotherapeutic agent for treatment of oral squamous cell carcinoma.
Literatur
1.
Zurück zum Zitat Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
2.
Zurück zum Zitat Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide: IARC cancer base No. 11 [Internet]. Lyon, France: International agency for research on cancer. Int J Cancer. 2015;127(12):2893–917.CrossRef Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide: IARC cancer base No. 11 [Internet]. Lyon, France: International agency for research on cancer. Int J Cancer. 2015;127(12):2893–917.CrossRef
3.
Zurück zum Zitat Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed
4.
Zurück zum Zitat Sturgis EM, Wei Q, Spitz MR. Descriptive epidemiology and risk factors for head and neck cancer. Semin Oncol. 2004;31(6):726–33.CrossRefPubMed Sturgis EM, Wei Q, Spitz MR. Descriptive epidemiology and risk factors for head and neck cancer. Semin Oncol. 2004;31(6):726–33.CrossRefPubMed
5.
Zurück zum Zitat Franceschi S, Bidoli E, Herrero R, Muñoz N. Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol. 2003;36(1):106–15.CrossRef Franceschi S, Bidoli E, Herrero R, Muñoz N. Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol. 2003;36(1):106–15.CrossRef
7.
Zurück zum Zitat Ahmad A, Sarkar SH, Bitar B, Ali S, Aboukameel A, Sethi S, et al. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther. 2012;11(10):2193–201.CrossRefPubMed Ahmad A, Sarkar SH, Bitar B, Ali S, Aboukameel A, Sethi S, et al. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther. 2012;11(10):2193–201.CrossRefPubMed
8.
Zurück zum Zitat Ahmad A, Sarkar SH, Aboukameel A, Ali S, Biersack B, Seibt S, et al. Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis. 2012;33(12):2450–6.CrossRefPubMed Ahmad A, Sarkar SH, Aboukameel A, Ali S, Biersack B, Seibt S, et al. Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis. 2012;33(12):2450–6.CrossRefPubMed
9.
Zurück zum Zitat Lee KW, Bode AM, Dong Z. Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer. 2011;11(3):211–8.CrossRefPubMed Lee KW, Bode AM, Dong Z. Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer. 2011;11(3):211–8.CrossRefPubMed
10.
Zurück zum Zitat Ahmad A, Wang Z, Wojewoda C, Ali R, Kong D, Maitah MY, et al. Garcinol-induced apoptosis in prostate and pancreatic cancer cells is mediated by NF- kappaB signaling. Front Biosci (Elite Ed). 2011;3:1483–92. Ahmad A, Wang Z, Wojewoda C, Ali R, Kong D, Maitah MY, et al. Garcinol-induced apoptosis in prostate and pancreatic cancer cells is mediated by NF- kappaB signaling. Front Biosci (Elite Ed). 2011;3:1483–92.
11.
Zurück zum Zitat Padhye S, Ahmad A, Oswal N, Sarkar FH. Emerging role of garcinol, the antioxidant chalcone from Garcinia indica choisy and its synthetic analogs. J Hematol Oncol. 2009;2:38.CrossRefPubMedPubMedCentral Padhye S, Ahmad A, Oswal N, Sarkar FH. Emerging role of garcinol, the antioxidant chalcone from Garcinia indica choisy and its synthetic analogs. J Hematol Oncol. 2009;2:38.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Parasramka MA, Gupta SV. Garcinol inhibits cell proliferation and promotes apoptosis in pancreatic adenocarcinoma cells. Nutr Cancer. 2011;63(3):456–65.CrossRefPubMed Parasramka MA, Gupta SV. Garcinol inhibits cell proliferation and promotes apoptosis in pancreatic adenocarcinoma cells. Nutr Cancer. 2011;63(3):456–65.CrossRefPubMed
13.
Zurück zum Zitat Pan MH, Chang WL, Lin-Shiau SY, Ho CT, Lin JK. Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. J Agric Food Chem. 2001;49(3):1464–74.CrossRefPubMed Pan MH, Chang WL, Lin-Shiau SY, Ho CT, Lin JK. Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. J Agric Food Chem. 2001;49(3):1464–74.CrossRefPubMed
14.
Zurück zum Zitat Sang S, Cheng X, Stark RE, Rosen RT, Yang CS, Ho C-T. Chemical studies on antioxidant mechanism of tea catechins: analysis of radical reaction products of catechin and epicatechin with 2,2-diphenyl-1-picrylhydrazyl. Bioorg Med Chem. 2002;10(7):2233–7.CrossRefPubMed Sang S, Cheng X, Stark RE, Rosen RT, Yang CS, Ho C-T. Chemical studies on antioxidant mechanism of tea catechins: analysis of radical reaction products of catechin and epicatechin with 2,2-diphenyl-1-picrylhydrazyl. Bioorg Med Chem. 2002;10(7):2233–7.CrossRefPubMed
15.
Zurück zum Zitat Rao AVR, Venkatswamy G, Pendse AD. Camboginol and cambogin. Tetrahedron Letters. 1980;21(20):1975–8.CrossRef Rao AVR, Venkatswamy G, Pendse AD. Camboginol and cambogin. Tetrahedron Letters. 1980;21(20):1975–8.CrossRef
16.
Zurück zum Zitat Ohnishi H, Asamoto M, Tujimura K, Hokaiwado N, Takahashi S, Ogawa K, et al. Inhibition of cell proliferation by nobiletin, a dietary phytochemical, associated with apoptosis and characteristic gene expression, but lack of effect on early rat hepatocarcinogenesis in vivo. Cancer Sci. 2004;95(12):936–42.CrossRefPubMed Ohnishi H, Asamoto M, Tujimura K, Hokaiwado N, Takahashi S, Ogawa K, et al. Inhibition of cell proliferation by nobiletin, a dietary phytochemical, associated with apoptosis and characteristic gene expression, but lack of effect on early rat hepatocarcinogenesis in vivo. Cancer Sci. 2004;95(12):936–42.CrossRefPubMed
17.
Zurück zum Zitat Ito C, Itoigawa M, Miyamoto Y, Onoda S, Rao KS, Mukainaka T, et al. Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities. J Nat Prod. 2003;66(2):206–9.CrossRefPubMed Ito C, Itoigawa M, Miyamoto Y, Onoda S, Rao KS, Mukainaka T, et al. Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities. J Nat Prod. 2003;66(2):206–9.CrossRefPubMed
18.
Zurück zum Zitat Tanaka T, Kohno H, Shimada R, Kagami S, Yamaguchi F, Kataoka S, et al. Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. Carcinogenesis. 2000;21(6):1183–9.CrossRefPubMed Tanaka T, Kohno H, Shimada R, Kagami S, Yamaguchi F, Kataoka S, et al. Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. Carcinogenesis. 2000;21(6):1183–9.CrossRefPubMed
19.
Zurück zum Zitat Prasad S, Ravindran J, Sung B, Pandey MK, Aggarwal BB. Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins. Mol Cancer Ther. 2010;9(4):856–68.CrossRefPubMedPubMedCentral Prasad S, Ravindran J, Sung B, Pandey MK, Aggarwal BB. Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins. Mol Cancer Ther. 2010;9(4):856–68.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Kapoor V, Singh AK, Dey S, Sharma SC, Das SN. Circulating cycloxygenase-2 in patients with tobacco-related intraoral squamous cell carcinoma and evaluation of its peptide inhibitors as potential antitumor agent. J Cancer Res Clin Oncol. 2010;136(12):1795–804.CrossRefPubMed Kapoor V, Singh AK, Dey S, Sharma SC, Das SN. Circulating cycloxygenase-2 in patients with tobacco-related intraoral squamous cell carcinoma and evaluation of its peptide inhibitors as potential antitumor agent. J Cancer Res Clin Oncol. 2010;136(12):1795–804.CrossRefPubMed
21.
Zurück zum Zitat Aggarwal S, Sharma SC, Das SN. Galectin-1 and galectin-3: plausible tumour markers for oral squamous cell carcinoma and suitable targets for screening high-risk population. Clin Chim Acta. 2015;442:13–21.CrossRefPubMed Aggarwal S, Sharma SC, Das SN. Galectin-1 and galectin-3: plausible tumour markers for oral squamous cell carcinoma and suitable targets for screening high-risk population. Clin Chim Acta. 2015;442:13–21.CrossRefPubMed
22.
Zurück zum Zitat Kapoor V, Zaharieva MM, Das SN, Berger MR. Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett. 2010;319(1):39–48.CrossRef Kapoor V, Zaharieva MM, Das SN, Berger MR. Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett. 2010;319(1):39–48.CrossRef
23.
Zurück zum Zitat Aggarwal S, Devaraja K, Sharma SC, Das SN. Expression of vascular endothelial growth factor (VEGF) in patients with oral squamous cell carcinoma and its clinical significance. Clin Chim Acta. 2014;436C:35–40.CrossRef Aggarwal S, Devaraja K, Sharma SC, Das SN. Expression of vascular endothelial growth factor (VEGF) in patients with oral squamous cell carcinoma and its clinical significance. Clin Chim Acta. 2014;436C:35–40.CrossRef
25.
Zurück zum Zitat Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem. 2004;279(32):33716–26.CrossRefPubMed Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem. 2004;279(32):33716–26.CrossRefPubMed
26.
Zurück zum Zitat Yoshida K, Tanaka T, Hirose Y, Yamaguchi F, Kohno H, Toida M, et al. Dietary garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in rats. Cancer Lett. 2005;221(1):29–39.CrossRefPubMed Yoshida K, Tanaka T, Hirose Y, Yamaguchi F, Kohno H, Toida M, et al. Dietary garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in rats. Cancer Lett. 2005;221(1):29–39.CrossRefPubMed
27.
Zurück zum Zitat Ye X, Yuan L, Zhang L, Zhao J, Zhang C-M, Deng H-Y. Garcinol, an acetyltransferase inhibitor, suppresses proliferation of breast cancer cell line MCF-7 promoted by 17β-estradiol. Asian Pac J Cancer Prev. 2014;15(12):5001–7.CrossRefPubMed Ye X, Yuan L, Zhang L, Zhao J, Zhang C-M, Deng H-Y. Garcinol, an acetyltransferase inhibitor, suppresses proliferation of breast cancer cell line MCF-7 promoted by 17β-estradiol. Asian Pac J Cancer Prev. 2014;15(12):5001–7.CrossRefPubMed
28.
Zurück zum Zitat Li F, Shanmugam MK, Siveen KS, Wang F, Ong TH, Loo SY, et al. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Oncotarget. 2015;6(7):5147–63.CrossRefPubMedPubMedCentral Li F, Shanmugam MK, Siveen KS, Wang F, Ong TH, Loo SY, et al. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Oncotarget. 2015;6(7):5147–63.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Hong J, Kwon SJ, Sang S, Ju J, Zhou J, Ho C-T, et al. Effects of garcinol and its derivatives on intestinal cell growth: inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free Radic Biol Med. 2007;42(8):1211–21.CrossRefPubMed Hong J, Kwon SJ, Sang S, Ju J, Zhou J, Ho C-T, et al. Effects of garcinol and its derivatives on intestinal cell growth: inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free Radic Biol Med. 2007;42(8):1211–21.CrossRefPubMed
30.
Zurück zum Zitat Ahmad A, Wang Z, Ali R, Maitah MY, Kong D, Banerjee S, et al. Apoptosis-inducing effect of garcinol is mediated by NF-kappaB signaling in breast cancer cells. J Cell Biochem. 2010;109(6):1134–41.PubMed Ahmad A, Wang Z, Ali R, Maitah MY, Kong D, Banerjee S, et al. Apoptosis-inducing effect of garcinol is mediated by NF-kappaB signaling in breast cancer cells. J Cell Biochem. 2010;109(6):1134–41.PubMed
31.
Zurück zum Zitat Matsumoto K, Akao Y, Kobayashi E, Ito T, Ohguchi K, Tanaka T, et al. Cytotoxic benzophenone derivatives from Garcinia species display a strong apoptosis-inducing effect against human leukemia cell lines. Biol Pharm Bull. 2003;26(4):569–71.CrossRefPubMed Matsumoto K, Akao Y, Kobayashi E, Ito T, Ohguchi K, Tanaka T, et al. Cytotoxic benzophenone derivatives from Garcinia species display a strong apoptosis-inducing effect against human leukemia cell lines. Biol Pharm Bull. 2003;26(4):569–71.CrossRefPubMed
32.
Zurück zum Zitat Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004;279(49):51163–71.CrossRefPubMed Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004;279(49):51163–71.CrossRefPubMed
33.
Zurück zum Zitat Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21(1):11–9.CrossRefPubMed Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21(1):11–9.CrossRefPubMed
34.
Zurück zum Zitat Bergmann F, Breinig M, Höpfner M, Rieker RJ, Fischer L, Köhler C, et al. Expression pattern and functional relevance of epidermal growth factor receptor and cyclooxygenase-2: novel chemotherapeutic targets in pancreatic endocrine tumors? Am J Gastroenterol. 2009;104(1):171–81.CrossRefPubMed Bergmann F, Breinig M, Höpfner M, Rieker RJ, Fischer L, Köhler C, et al. Expression pattern and functional relevance of epidermal growth factor receptor and cyclooxygenase-2: novel chemotherapeutic targets in pancreatic endocrine tumors? Am J Gastroenterol. 2009;104(1):171–81.CrossRefPubMed
35.
Zurück zum Zitat Sarkar FH, Adsule S, Li Y, Padhye S. Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007;7(6):599–608.CrossRefPubMed Sarkar FH, Adsule S, Li Y, Padhye S. Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007;7(6):599–608.CrossRefPubMed
36.
Zurück zum Zitat Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol. 2003;4(10):605–15.CrossRefPubMed Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol. 2003;4(10):605–15.CrossRefPubMed
Metadaten
Titel
Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer
verfasst von
Sadhna Aggarwal
Satya N. Das
Publikationsdatum
12.12.2015
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 6/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4583-8

Weitere Artikel der Ausgabe 6/2016

Tumor Biology 6/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.