Abstract
Metabolic plasticity in cancer cells assures cell survival and cell proliferation under variable levels of oxygen and nutrients. Therefore, new anticancer treatments endeavor to target such plasticity by modifying main metabolic pathways as glycolysis or oxidative phosphorylation. In American traditional medicine Petiveria alliacea L., Phytolaccacea, leaf extracts have been used for leukemia and breast cancer treatments. Herein, we study cytotoxicity and antitumoral effects of P. alliacea extract in tumor/non-tumorigenic cell lines and murine breast cancer model. Breast cancer cells treated with P. alliacea dry extract showed reduction in β-F1-ATPase expression, glycolytic flux triggering diminished intracellular ATP levels, mitochondrial basal respiration and oxygen consumption. Consequently, a decline in cell proliferation was observed in conventional and three-dimension spheres breast cancer cells culture. Additionally, in vivo treatment of BALB/c mice transplanted with the murine breast cancer TS/A tumor showed that P. alliacea extract via i.p. decreases the primary tumor growth and increases survival in the TS/A model.
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Acebo, P., Giner, D., Calvo, P., Blanco-Rivero, A., Ortega, Á.D., Fernández, P.L., Roncador, G., Fernández-Malavé, E., Chamorro, M., Cuezva, J.M., 2009. Cancer abolishes the tissue type-specific differences in the phenotype of energetic metabolism. Transl. Oncol. 2, 138–145.
Chen, V., Staub, R.E., Fong, S., Tagliaferri, M., Cohen, I., Shtivelman, E., 2012. Bezielle selectively targets mitochondriaof cancer cells to inhibit glycolysis and OXPHOS. PLoS ONE 7, e30300.
Chirinos, D.N., 1992. El milagro de los vegetales: Petiveria alliacea, 3rd ed. Bienes Lacónica, Caracas, Venezuela.
Ciavardelli, D., Rossi, C., Barcaroli, D., Volpe, S., Consalvo, A., Zucchelli, M., De Cola, A., Scavo, E., Carollo, R., D’Agostino, D., Forli, F., D’Aguanno, S., Todaro, M., Stassi, G., Di Ilio, C., De Laurenzi, V., Urbani, A., 2014. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment. Cell Death Dis. 5, e1336.
Cifuentes, C., Castaneda, D., Urueña, C., Fiorentino, S., 2009. A fraction from Petiveria alliacea induces apoptosis via a mitochondria dependent pathway and regulates Hsp70 expression. Universitas Sci. 14, 125–134.
Correa, J., Bernal, H., 1998. Especies Vegetales Promisorias de Paises del convenio Andrés Bello, Bogotá, Colombia.
Cuezva, J., Krajewska, M., de Heredia, M., Krajewski, S., Santamaria, G., Kim, H., Zapata, J., Marusawa, H., Chamorro, M., Reed, J., 2002. The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res. 62, 6674–6681.
Cuezva, J.M., Ortega, A., Willers, I., Sanchez-Cenizo, L., Aldea, M., Sanchez-Arago, M., 2009. The tumor suppressor function of mitochondria: translation into the clinics. Biochim. Biophys. Acta 1792, 1145–1158.
Fantin, V., St-Pierre, J., Leder, P., 2006. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434.
Formentini, L., Martínez-Reyes, I., Cuezva, J., 2010. The mitochondrial bioenergetic capacity of carcinomas. IUBMB Life 62, 554–560.
Garcia-Barriga, H., 1974. Flora Medicinal de Colombia. Instituto de Ciencias Natu-rales. Universidad Nacional, Bogotá, Colombia.
Gledhill, J., Montgomery, M., Leslie, A., Walker, J., 2007. Mechanism of inhibition of bovine Fl-ATPase by resveratrol and related polyphenols. PNAS 104, 13632–13637.
Gong, C., Bauvy, C., Tonelli, G., Yue, W., Delomenie, C., Nicolas, V., Zhu, Y., Domergue, V., Marin-Esteban, V., Tharinger, H., Delbos, L., Gary-Gouy, H., Morel, A., Ghavami, S., Song, E., Codogno, P., Mehrpour, M., 2013. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene 32, 2261–2272.
Govindarajan, B., Sligh, J., Vincent, B., Li, M., Canter, J., Nickoloff, B., Rodenburg, R., Smeitink, J., Oberley, L., Zhang, Y., Slingerland, J., Arnold, R., Lambeth, J., Cohen, C., Hilenski, L., Griendling, It, Martinez-Diez, M., Cuezva, J., Arbiser, J., 2007. Overex-pression of Akt converts radial growth melanoma to vertical growth melanoma. J. Clin. Invest. 117, 719–729.
Gupta, M., 1995. 270 Plantas medicinales Iberoamericanas. Convenio Andrés Bello. Convenio Andres Bello y Subprograma X del CYTED, Bogota, Colombia.
Hernandez, J., Urueña, C., Cifuentes, C., Sandoval, T., Pombo, L., Castaneda, D., Asea, A., Fiorentino, S., 2014. A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism. J. Ethnopharmacol. 153, 641–649.
Jose, C., Rossignol, R., 2013. Rationale for mitochondria-targeting strategies in cancer bioenergetic therapies. Int. J. Biochem. Cell Biol. 45, 123–129.
Koukourakis, M., Kontomanolis, E., Giatromanolaki, A., Sivridis, E., Liberis, V., 2008. Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol. Obstet. Invest. 67, 162–168.
Leist, M., Single, B., Castoldi, A.S., Kuhnle, S., Nicotera, P., 1997. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185, 1481–1486.
Morales, C., Gomez-Serranillos, M., Iglesias, I., Villar, A., Caceres, A., 2001. Preliminary screening of five ethnomedicinal plants of Guatemala. Farmaco 56, 523–526.
Nanni, P., de Giovanni, C., Lollini, P., Nicoletti, G., Prodi, G., 1983. TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin. Exp. Metastasis 1, 373–380.
Pampaloni, F., Reynaud, E., Stelzer, E., 2007. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8, 839–845.
Papandreou, I., Goliasova, T., Denko, N., 2011. Anticancer drugs that target metabolism: is dichloroacetate the new paradigm? Int. J. Cancer 128, 1001–1008.
Rossi, V., 1990. Antiproliferative effects of Petiveria alliacea on several tumoral lines. Pharmacol. Res. 22, 434.
Rossi, V., Marini, S., Jovicevic, L., D’Atri, S., Turri, M., Giardina, B., 1993. Effects of Petiveria alliacea L. on cell immunity. Pharmacol. Res. 27 (Supplement 1), 111–112.
Stock, D., Leslie, A., Walker, J., 1999. Molecular architecture of the rotary motor in ATP synthase. Science 286, 1700–1705.
Suolinna, E., Buchsbaum, R., Racker, E., 1975. The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res. 35, 1865–1872.
Urueña, C., Cifuentes, C., Castaneda, D., Arango, A., Kaur, P., Asea, A., Fiorentino, S., 2008. Petiveria alliacea extracts uses multiple mechanisms to inhibit growth of human and mouse tumoral cells. BMC Complement. Altern. Med. 8, https://doi.org/10.1186/1472-6882-8-60.
Urueña, C., Mancipe, J., Hernandez, J., Castaneda, D., Pombo, L., Gomez, Asea, A., Fiorentino, S., 2013. Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model. BMC Complement. Altern. Med. 13, https://doi.org/10.1186/1472-6882-13-74.
Willers, L., Cuezva, J., 2011. Post-transcriptional regulation of the mitochondrial H+ATP synthase: a key regulator of the metabolic phenotype in cancer. Biochim. Biophys. Acta 1807, 543–551.
Zhang, X., Fryknäs, M., Hernlund, E., Fayad, W., De Milito, A., Olofsson, M., Gogvadze, V., Dang, L., Påhlman, S., Schughart, L., 2014. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat. Commun. 5, https://doi.org/10.1038/ncomms4295.
Zheng, J., Ramirez, V., 2000. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenols phytochemicals. Br. J. Pharmacol. 130, 1115–1123.
Zhou, M., Zhao, Y., Ding, Y., Liu, H., Liu, Z., Fodstad, O., Riker, A., Kamarajugadda, S., Lu, J., Owen, L., 2010. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol. Cancer 9, https://doi.org/10.1186/1476-4598-9-33.
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SF, JMC, LF and JFH participate in the study conception and experiments design. JFH and TAS perform the acquisition of data. JFH, CPU, MCC and TAS participate in drafting of manuscript. SF, MCC and JMC accomplish the critical revision of manuscript. All the authors contribute to analysis and interpretation of data.
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Hernández, J.F., Urueña, C.P., Sandoval, T.A. et al. A cytotoxic Petiveria alliacea dry extract induces ATP depletion and decreases β-F1-ATPase expression in breast cancer cells and promotes survival in tumor-bearing mice. Rev. Bras. Farmacogn. 27, 306–314 (2017). https://doi.org/10.1016/j.bjp.2016.09.008
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DOI: https://doi.org/10.1016/j.bjp.2016.09.008