[10]-Gingerol Affects Multiple Metastatic Processes and Induces Apoptosis in MDAMB- 231 Breast Tumor Cells

Author(s): Angelina M. Fuzer, Ana C.B.M. Martin, Amanda B. Becceneri, James A. da Silva, Paulo C. Vieira, Marcia R. Cominetti*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 5 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Triple Negative Breast Cancer (TNBC) represents the approximately 15% of breast cancers that lack expression of Estrogen (ER) and Progesterone Receptors (PR) and do not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene, imposing difficulties to treatment. Interactions between tumor cells and their microenvironment facilitate tumor cell invasion in the surrounding tissues, intravasation through newly formed vessels, and dissemination to form metastasis. To treat metastasis from breast and many other cancer types, chemotherapy is one of the most extensively used methods. However, its efficacy and safety remain a primary concern, as well as its toxicity and other side effects. Thus, there is increasing interest in natural antitumor agents. In a previous work, we have demonstrated that [10]-gingerol is able to revert malignant phenotype in breast cancer cells in 3D culture and, moreover, to inhibit the dissemination of TNBC to multiple organs including lung, bone and brain, in spontaneous and experimental in vivo metastasis assays in mouse model.

Objectives: This work aims to investigate the in vitro effects of [10]-gingerol, using human MDA-MB-231TNBC cells, in comparison to non-tumor MCF-10A breast cells, in order to understand the antitumor and antimetastatic effects found in vivo and in a 3D environment.

Methods: We investigated different steps of the metastatic process in vitro, such as cell migration, invasion, adhesion and MMP activity. In addition, we analyzed the anti-apoptotic and genotoxic effects of [10]-gingerol using PEAnnexin, DNA fragmentation, TUNEL and comet assays, respectively.

Results: [10]-gingerol was able to inhibit cell adhesion, migration, invasion and to induce apoptosis more effectively in TNBC cells, when compared to non-tumor cells, demonstrating that these mechanisms can be involved in the antitumor and antimetastatic effects of [10]-gingerol, found both in 3D culture and in vivo.

Conclusion: Taken together, results found here are complementary to previous studies of our group and others and demonstrate that additional mechanisms, besides apoptotic cell death, is used by [10]-gingerol to accomplish its antitumor and antimetastatic effects. Our results indicate a potential for this natural compound as an antitumor molecule or as an adjuvant for chemotherapeutics already used in the clinic.

Keywords: Apoptosis, breast cancer, [10]-gingerol, ginger, metastasis, natural product, triple negative breast cancer.

WHO. World Cancer Report 2014; International Agency for Research on Cancer: Geneva, Switzerland, 2014, p. 630.
WHO, WHO Projections of mortality and causes of death 2015 and 2030. 2015.
Stuckey, A. Breast cancer: Epidemiology and risk factors. Clin. Obstet. Gynecol., 2011, 54(1), 96-102.
Criscitiello, C.; Azim, H.A., Jr; Schouten, P.C.; Linn, S.C.; Sotiriou, C. Understanding the biology of triple-negative breast cancer. Ann. Oncol., 2012, 23(Suppl. 6), vi13-vi18.
Prouse, J. The impact of methods of information on chemotherapy-related side effects. Clin. J. Oncol. Nurs., 2010, 14(2), 206-211.
Rivera, E.; Gomez, H. Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res., 2010, 12(Suppl. 2), S2.
Froidevaux-Klipfel, L.; Poirier, F.; Boursier, C.; Crepin, R.; Pous, C.; Baudin, B.; Baillet, A. Modulation of septin and molecular motor recruitment in the microtubule environment of the Taxol-resistant human breast cancer cell line MDA-MB-231. Proteomics, 2011, 11(19), 3877-3886.
Demain, A.L.; Vaishnav, P. Natural products for cancer chemotherapy. Microb. Biotechnol., 2010, 4(6), 687-699.
Dugasani, S.; Pichika, M.R.; Nadarajah, V.D.; Balijepalli, M.K.; Tandra, S.; Korlakunta, J.N. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J. Ethnopharmacol., 2010, 127(2), 515-520.
Sang, S.; Hong, J.; Wu, H.; Liu, J.; Yang, C.S.; Pan, M.H.; Badmaev, V.; Ho, C.T. Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols. J. Agric. Food Chem., 2009, 57(22), 10645-10650.
Poltronieri, J.; Becceneri, A.B.; Fuzer, A.M.; Filho, J.C.; Martin, A.C.; Vieira, P.C.; Pouliot, N.; Cominetti, M.R. [6]-gingerol as a cancer chemopreventive agent: A review of its activity on different steps of the metastatic process. Mini Rev. Med. Chem., 2014, 14(4), 313-321.
Chen, C.Y.; Li, Y.W.; Kuo, S.Y. Effect of [10]-gingerol on [Ca2+] i and cell death in human colorectal cancer cells. Molecules, 2009, 14(3), 959-969.
Ryu, M.J.; Chung, H.S. [10]-Gingerol induces mitochondrial apoptosis through activation of MAPK pathway in HCT116 human colon cancer cells. In Vitro Cell. Dev. Biol. Anim., 2015, 51(1), 92-101.
Fuzer, A.M.; Lee, S.Y.; Mott, J.D.; Cominetti, M.R. [10]-Gingerol reverts malignant phenotype of breast cancer cells in 3D culture. J. Cell. Biochem., 2017, 118(9), 2693-2699.
Martin, A.; Fuzer, A.M.; Becceneri, A.B.; da Silva, J.A.; Tomasin, R.; Denoyer, D.; Kim, S.H.; McIntyre, K.A.; Pearson, H.B.; Yeo, B.; Nagpal, A.; Ling, X.; Selistre-de-Araujo, H.S.; Vieira, P.C.; Cominetti, M.R.; Pouliot, N. [10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo. Oncotarget, 2017, 8(42), 72260-72271.
Almada-da-Silva, J.; Becceneri, A.B.; Sanches Mutti, H.; Moreno Martin, A.C.; Fernandes da Silva, M.F.; Fernandes, J.B.; Vieira, P.C.; Cominetti, M.R. Purification and differential biological effects of ginger-derived substances on normal and tumor cell lines. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 903, 157-162.
Tice, R.R.; Agurell, E.; Anderson, D.; Burlinson, B.; Hartmann, A.; Kobayashi, H.; Miyamae, Y.; Rojas, E.; Ryu, J.C.; Sasaki, Y.F. Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing. Environ. Mol. Mutagen., 2000, 35(3), 206-221.
Helma, C.; Uhl, M. A public domain image-analysis program for the single-cell gel-electrophoresis (comet) assay. Mutat. Res., 2000, 466(1), 9-15.
Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 1970, 227(5259), 680-685.
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 2001, 25(4), 402-408.
Bustin, S.A.; Benes, V.; Garson, J.A.; Hellemans, J.; Huggett, J.; Kubista, M.; Mueller, R.; Nolan, T.; Pfaffl, M.W.; Shipley, G.L.; Vandesompele, J.; Wittwer, C.T. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin. Chem., 2009, 55(4), 611-622.
Chia, J.; Kusuma, N.; Anderson, R.; Parker, B.; Bidwell, B.; Zamurs, L.; Nice, E.; Pouliot, N. Evidence for a role of tumor-derived laminin-511 in the metastatic progression of breast cancer. Am. J. Pathol., 2007, 170(6), 2135-2148.
Yue, P.Y.; Leung, E.P.; Mak, N.K.; Wong, R.N. A simplified method for quantifying cell migration/wound healing in 96-well plates. J. Biomol. Screen., 2010, 15(4), 427-433.
Babykutty, S.; Kumar, M.S.; Nair, M.S.; Srinivas, P.; Gopala, S. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-kappaB in colon cancer cells. Mol. Carcinog., 2012, 51(6), 475-490.
Leber, T.M.; Negus, R.P. Detection and quantitation of matrix metalloproteases by zymography. Methods Mol. Med., 2001, 39, 509-514.
Rattarom, R.; Sakpakdeejaroen, I.; Hansakul, P.; Itharat, A. Cytotoxic activity against small cell lung cancer cell line and chromatographic fingerprinting of six isolated compounds from the ethanolic extract of Benjakul. J. Med. Assoc. Thai., 2014, 97(Suppl. 8), S70-S75.
Coghi, P.; Yaremenko, I.A.; Prommana, P.; Radulov, P.S.; Syroeshkin, M.A.; Wu, Y.J.; Gao, J.Y.; Gordillo, F.M.; Mok, S.; Wong, V.K.W.; Uthaipibull, C.; Terent’ev, A.O. Novel peroxides as promising anticancer agents with unexpected depressed antimalarial activity. ChemMedChem, 2018, 13(9), 902-908.
Hassan, M.; Watari, H.; Abu-Almaaty, A.; Ohba, Y.; Sakuragi, N. Apoptosis and molecular targeting therapy in cancer. BioMed Res. Int., 2014, 2014150845
Norbury, C.J.; Zhivotovsky, B. DNA damage-induced apoptosis. Oncogene, 2004, 23(16), 2797-2808.
Bernard, M.M.; McConnery, J.R.; Hoskin, D.W. [10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells. Exp. Mol. Pathol., 2017, 102(2), 370-376.
Ryu, M.J.; Chung, H.S. [10]-Gingerol induces mitochondrial apoptosis through activation of MAPK pathway in HCT116 human colon cancer cells. In Vitro Cell. Dev. Biol. Anim., 2015, 51(1), 92-101.
Hood, J.D.; Cheresh, D.A. Role of integrins in cell invasion and migration. Nat. Rev. Cancer, 2002, 2(2), 91-100.
Cheung, K.J.; Ewald, A.J. Illuminating breast cancer invasion: Diverse roles for cell-cell interactions. Curr. Opin. Cell Biol., 2014, 30, 99-111.
Vandooren, J.; Van den Steen, P.E.; Opdenakker, G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade. Crit. Rev. Biochem. Mol. Biol., 2013, 48(3), 222-272.
Joo, J.H.; Hong, S.S.; Cho, Y.R.; Seo, D.W. 10-Gingerol inhibits proliferation and invasion of MDA-MB-231 breast cancer cells through suppression of Akt and p38MAPK activity. Oncol. Rep., 2016, 35(2), 779-784.
Yagihashi, S.; Miura, Y.; Yagasaki, K. Inhibitory effect of gingerol on the proliferation and invasion of hepatoma cells in culture. Cytotechnology, 2008, 57(2), 129-136.
Weng, C.J.; Wu, C.F.; Huang, H.W.; Ho, C.T.; Yen, G.C. Anti-invasion effects of 6-shogaol and 6-gingerol, two active components in ginger, on human hepatocarcinoma cells. Mol. Nutr. Food Res., 2010, 54(11), 1618-1627.
Arjonen, A.; Kaukonen, R.; Ivaska, J. Filopodia and adhesion in cancer cell motility. Cell Adhes. Migr., 2011, 5(5), 421-430.
Lee, H.S.; Seo, E.Y.; Kang, N.E.; Kim, W.K. [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells. J. Nutr. Biochem., 2008, 19(5), 313-319.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 26 June, 2019
Page: [645 - 654]
Pages: 10
DOI: 10.2174/1871520618666181029125607
Price: $65

Article Metrics

PDF: 53