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Piper nigrum ethanolic extract rich in piperamides causes ROS overproduction, oxidative damage in DNA leading to cell cycle arrest and apoptosis in cancer cells.
J Ethnopharmacol. 2016 Aug 02; 189:139-47.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Ayurvedic and Chinese traditional medicine and tribal people use herbal preparations containing Piper nigrum fruits for the treatment of many health disorders like inflammation, fever, asthma and cancer. In Brazil, traditional maroon culture associates the spice Piper nigrum to health recovery and inflammation attenuation.

AIMS OF THE STUDY

The aim of the current work was to evaluate the relationship between reactive oxygen species (ROS) overproduction, DNA fragmentation, cell cycle arrest and apoptosis induced by Piper nigrum ethanolic extract and its antitumor activity.

METHODS

The plant was macerated in ethanol. Extract constitution was assessed by TLC, UV-vis and ESI-IT-MS/MS spectrometry. The cytotoxicity, proliferation and intracellular ROS generation was evaluated in MCF-7 cells. DNA damage effects were evaluated through intercalation into CT-DNA, plasmid DNA cleavage and oxidative damage in CT-DNA. Tumor growth inhibition, survival time increase, apoptosis, cell cycle arrest and oxidative stress were assessed in Ehrlich ascites carcinoma-bearing mice.

RESULTS

Extraction yielded 64mg/g (36% piperine and 4.2% piperyline). Treatments caused DNA damage and reduced cell viability (EC50=27.1±2.0 and 80.5±6.6µg/ml in MCF-7 and HT-29 cells, respectively), inhibiting cell proliferation by 57% and increased ROS generation in MCF-7 cells (65%). Ehrlich carcinoma was inhibited by the extract, which caused reduction of tumor growth (60%), elevated survival time (76%), cell cycle arrest and induced apoptosis. The treatment with extract increased Bax and p53 and inhibited Bcl-xL and cyclin A expression. It also induced an oxidative stress in vivo verified as enhanced lipid peroxidation and carbonyl proteins content and increased activities of glutathione reductase, superoxide dismutase and catalase. GSH concentration was decreased in tumor tissue from mice.

CONCLUSION

The ethanolic extract has cytotoxic and antiproliferative effect on MCF-7 cells and antitumor effect in vivo probably due to ROS overproduction that induced oxidative stress affecting key proteins involved in cell cycle arrest at G1/S and triggering apoptosis. Finally, the overall data from this study are well in line with the traditional claims for the antitumor effect of Piper nigrum fruits.

Authors+Show Affiliations

Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Programa de Pós-Graduação em Ciências da Saúde da Universidade do Sul de Santa Catarina (UNISUL), SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.Departamento de Ecologia e Zoologia,Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.NITBIO, Universidade Federal de Santa Catarina, Araranguá, SC, Brazil.Laboratório de Bioquímica Experimental, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: rozangela.pedrosa@ufsc.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27178634

Citation

de Souza Grinevicius, Valdelúcia Maria Alves, et al. "Piper Nigrum Ethanolic Extract Rich in Piperamides Causes ROS Overproduction, Oxidative Damage in DNA Leading to Cell Cycle Arrest and Apoptosis in Cancer Cells." Journal of Ethnopharmacology, vol. 189, 2016, pp. 139-47.
de Souza Grinevicius VM, Kviecinski MR, Santos Mota NS, et al. Piper nigrum ethanolic extract rich in piperamides causes ROS overproduction, oxidative damage in DNA leading to cell cycle arrest and apoptosis in cancer cells. J Ethnopharmacol. 2016;189:139-47.
de Souza Grinevicius, V. M., Kviecinski, M. R., Santos Mota, N. S., Ourique, F., Porfirio Will Castro, L. S., Andreguetti, R. R., Gomes Correia, J. F., Filho, D. W., Pich, C. T., & Pedrosa, R. C. (2016). Piper nigrum ethanolic extract rich in piperamides causes ROS overproduction, oxidative damage in DNA leading to cell cycle arrest and apoptosis in cancer cells. Journal of Ethnopharmacology, 189, 139-47. https://doi.org/10.1016/j.jep.2016.05.020
de Souza Grinevicius VM, et al. Piper Nigrum Ethanolic Extract Rich in Piperamides Causes ROS Overproduction, Oxidative Damage in DNA Leading to Cell Cycle Arrest and Apoptosis in Cancer Cells. J Ethnopharmacol. 2016 Aug 2;189:139-47. PubMed PMID: 27178634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Piper nigrum ethanolic extract rich in piperamides causes ROS overproduction, oxidative damage in DNA leading to cell cycle arrest and apoptosis in cancer cells. AU - de Souza Grinevicius,Valdelúcia Maria Alves, AU - Kviecinski,Maicon Roberto, AU - Santos Mota,Nádia Sandrini Ramos, AU - Ourique,Fabiana, AU - Porfirio Will Castro,Luiza Sheyla Evenni, AU - Andreguetti,Rafaela Rafognato, AU - Gomes Correia,João Francisco, AU - Filho,Danilo Wilhem, AU - Pich,Claus Tröger, AU - Pedrosa,Rozangela Curi, Y1 - 2016/05/10/ PY - 2015/05/18/received PY - 2016/05/05/revised PY - 2016/05/09/accepted PY - 2016/5/15/entrez PY - 2016/5/15/pubmed PY - 2017/4/21/medline KW - Antitumor activity KW - Apoptosis KW - Cell cycle arrest KW - DNA damage KW - Doxorubicin (PubChem CID: 31703) KW - Piper nigrum KW - Piperine (PubChem CID: 638024) KW - Piperyline (PubChem CID: 636537) KW - ROS overproduction SP - 139 EP - 47 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 189 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Ayurvedic and Chinese traditional medicine and tribal people use herbal preparations containing Piper nigrum fruits for the treatment of many health disorders like inflammation, fever, asthma and cancer. In Brazil, traditional maroon culture associates the spice Piper nigrum to health recovery and inflammation attenuation. AIMS OF THE STUDY: The aim of the current work was to evaluate the relationship between reactive oxygen species (ROS) overproduction, DNA fragmentation, cell cycle arrest and apoptosis induced by Piper nigrum ethanolic extract and its antitumor activity. METHODS: The plant was macerated in ethanol. Extract constitution was assessed by TLC, UV-vis and ESI-IT-MS/MS spectrometry. The cytotoxicity, proliferation and intracellular ROS generation was evaluated in MCF-7 cells. DNA damage effects were evaluated through intercalation into CT-DNA, plasmid DNA cleavage and oxidative damage in CT-DNA. Tumor growth inhibition, survival time increase, apoptosis, cell cycle arrest and oxidative stress were assessed in Ehrlich ascites carcinoma-bearing mice. RESULTS: Extraction yielded 64mg/g (36% piperine and 4.2% piperyline). Treatments caused DNA damage and reduced cell viability (EC50=27.1±2.0 and 80.5±6.6µg/ml in MCF-7 and HT-29 cells, respectively), inhibiting cell proliferation by 57% and increased ROS generation in MCF-7 cells (65%). Ehrlich carcinoma was inhibited by the extract, which caused reduction of tumor growth (60%), elevated survival time (76%), cell cycle arrest and induced apoptosis. The treatment with extract increased Bax and p53 and inhibited Bcl-xL and cyclin A expression. It also induced an oxidative stress in vivo verified as enhanced lipid peroxidation and carbonyl proteins content and increased activities of glutathione reductase, superoxide dismutase and catalase. GSH concentration was decreased in tumor tissue from mice. CONCLUSION: The ethanolic extract has cytotoxic and antiproliferative effect on MCF-7 cells and antitumor effect in vivo probably due to ROS overproduction that induced oxidative stress affecting key proteins involved in cell cycle arrest at G1/S and triggering apoptosis. Finally, the overall data from this study are well in line with the traditional claims for the antitumor effect of Piper nigrum fruits. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/27178634/Piper_nigrum_ethanolic_extract_rich_in_piperamides_causes_ROS_overproduction_oxidative_damage_in_DNA_leading_to_cell_cycle_arrest_and_apoptosis_in_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(16)30291-4 DB - PRIME DP - Unbound Medicine ER -