Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2020

Open Access 01-12-2020 | Colon Cancer | Research article

6-Shogaol enhances the anticancer effect of 5-fluorouracil, oxaliplatin, and irinotecan via increase of apoptosis and autophagy in colon cancer cells in hypoxic/aglycemic conditions

Authors: Marta Woźniak, Sebastian Makuch, Kinga Winograd, Jerzy Wiśniewski, Piotr Ziółkowski, Siddarth Agrawal

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

Login to get access

Abstract

Background

The development and growth of colorectal cancer based on constitutive activation of numerous signaling pathways that stimulate proliferation and metastasis. Plant-derived agents excel by targeting multiple aspects of tumor progression. Previous investigations have shown that ginger derivatives- shogaols possess anti-cancer and anti-inflammatory effects. In the present study, we have examined the anti-cancer effects of 6-shogaol alongside with the most widely used chemotherapeutic agents/regimens in the tumor-like microenvironment conditions.

Methods

Cytotoxicity on two colon cancer cell lines (SW480 and SW620) was measured by MTT test. Apoptosisassay, immunocytochemical and Western blotting analysis for autophagy and apoptosis detection were performed.

Results

Here, we report that 6-shogaol by itself or in combination with chemotherapeutic agents/regimens exerted a cytotoxic effect on CRC cells. Cell death might be linked with the activation of autophagy and apoptosis-related pathways. In the tumor-like microenvironment, which is characterized by hypoxia and glucose starvation, 6-shogaol with chemotherapeutics is significantly more potent than conventional chemotherapy alone.

Conclusions

Collectively, our data suggest that the addition of 6-shogaol to established chemotherapeutic regimens could potentially be a remarkable therapeutic strategy for colorectal cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRef Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRef
2.
go back to reference Torre LA, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef Torre LA, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef
3.
go back to reference O’dwyer ST, Renehan AG, Zwahlen M, Egger M. Risk of second primary colorectal cancer with particular reference to age at diagnosis. Color Dis. 2007;9:186.CrossRef O’dwyer ST, Renehan AG, Zwahlen M, Egger M. Risk of second primary colorectal cancer with particular reference to age at diagnosis. Color Dis. 2007;9:186.CrossRef
4.
go back to reference André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.CrossRef André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.CrossRef
6.
go back to reference Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res. 2010;16:5972–80.CrossRef Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res. 2010;16:5972–80.CrossRef
7.
go back to reference McCarty MF. Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. Integr Cancer Ther. 2004;3:349–80.CrossRef McCarty MF. Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. Integr Cancer Ther. 2004;3:349–80.CrossRef
8.
go back to reference Hu X, Chao M, Wu H. Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation. Signal Transd Target Ther. 2017;2:16047.CrossRef Hu X, Chao M, Wu H. Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation. Signal Transd Target Ther. 2017;2:16047.CrossRef
9.
go back to reference Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18(1):157.CrossRef Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18(1):157.CrossRef
10.
go back to reference Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 2011;14(3):191–201.CrossRef Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 2011;14(3):191–201.CrossRef
11.
go back to reference Yang G, Xu S, Peng L, et al. The hypoxia-mimetic agent CoCl2 induces chemotherapy resistance in LOVO colorectal cancer cells. Mol Med Rep. 2016;13(3):2583–9.CrossRef Yang G, Xu S, Peng L, et al. The hypoxia-mimetic agent CoCl2 induces chemotherapy resistance in LOVO colorectal cancer cells. Mol Med Rep. 2016;13(3):2583–9.CrossRef
12.
go back to reference Saint-Martin A, Martínez-Ríos J, Castañeda-Patlán MC, et al. Functional interaction of hypoxia-inducible factor 2-alpha and autophagy mediates drug resistance in colon cancer cells. Cancers. 2019;11:6. Saint-Martin A, Martínez-Ríos J, Castañeda-Patlán MC, et al. Functional interaction of hypoxia-inducible factor 2-alpha and autophagy mediates drug resistance in colon cancer cells. Cancers. 2019;11:6.
13.
go back to reference Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a unique target for tumor therapy. Cancer Cell Int. 2016;16:49.CrossRef Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a unique target for tumor therapy. Cancer Cell Int. 2016;16:49.CrossRef
14.
go back to reference Safe S, Kasiappan R. Natural products as mechanism-based anticancer agents: Sp transcription factors as targets. Phytother Res. 2016;30:1723–32.CrossRef Safe S, Kasiappan R. Natural products as mechanism-based anticancer agents: Sp transcription factors as targets. Phytother Res. 2016;30:1723–32.CrossRef
15.
go back to reference Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008;46:409–20.CrossRef Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008;46:409–20.CrossRef
16.
go back to reference Pan MH, Hsieh MC, Kuo JM, Lai CS, Wu H, Sang S, Ho CT. 6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression. Mol Nutr Food Res. 2008;52:527–37.CrossRef Pan MH, Hsieh MC, Kuo JM, Lai CS, Wu H, Sang S, Ho CT. 6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression. Mol Nutr Food Res. 2008;52:527–37.CrossRef
17.
go back to reference Kim SM, Kim C, Bae H, Lee JH, Baek SH, Nam D, Chung WS, Shim BS, Lee SG, Kim SH, Sethi G, Ahn KS. 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways. Mol Carcinog. 2015;54:1132–46.CrossRef Kim SM, Kim C, Bae H, Lee JH, Baek SH, Nam D, Chung WS, Shim BS, Lee SG, Kim SH, Sethi G, Ahn KS. 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways. Mol Carcinog. 2015;54:1132–46.CrossRef
18.
go back to reference Annamalai G, Kathiresan S, Kannappan N. [6]-Shogaol, a dietary phenolic compound, induces oxidative stress mediated mitochondrial dependant apoptosis through activation of proapoptotic factors in Hep-2 cells. Biomed Pharmacother. 2016;82:226–36.CrossRef Annamalai G, Kathiresan S, Kannappan N. [6]-Shogaol, a dietary phenolic compound, induces oxidative stress mediated mitochondrial dependant apoptosis through activation of proapoptotic factors in Hep-2 cells. Biomed Pharmacother. 2016;82:226–36.CrossRef
19.
go back to reference Warin RF, Chen H, Soroka DN, Zhu Y, Sang S. Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteineconjugated metabolite M2. J Agric Food Chem. 2014;62:1352–62.CrossRef Warin RF, Chen H, Soroka DN, Zhu Y, Sang S. Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteineconjugated metabolite M2. J Agric Food Chem. 2014;62:1352–62.CrossRef
20.
go back to reference Hung JY, Hsu YL, Li CT, Ko YC, Ni WC, Huang MS, Kuo PL. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem. 2009;57:9809–16.CrossRef Hung JY, Hsu YL, Li CT, Ko YC, Ni WC, Huang MS, Kuo PL. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem. 2009;57:9809–16.CrossRef
21.
go back to reference Ray A, Vasudevan S, Sengupta S. 6-Shogaol inhibits breast cancer cells and stem cell-like spheroids by modulation of Notch signaling pathway and induction of autophagic cell death. PLoS One. 2015;10:e0137614.CrossRef Ray A, Vasudevan S, Sengupta S. 6-Shogaol inhibits breast cancer cells and stem cell-like spheroids by modulation of Notch signaling pathway and induction of autophagic cell death. PLoS One. 2015;10:e0137614.CrossRef
22.
go back to reference Li TY, Chiang BH. 6-shogaol induces autophagic cell death then triggered apoptosis in colorectal adenocarcinoma HT-29 cells. Biomed Pharmacother. 2017;93:208–17.CrossRef Li TY, Chiang BH. 6-shogaol induces autophagic cell death then triggered apoptosis in colorectal adenocarcinoma HT-29 cells. Biomed Pharmacother. 2017;93:208–17.CrossRef
23.
go back to reference Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14:1–10.CrossRef Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015;14:1–10.CrossRef
24.
go back to reference Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol. 2016;22:6876.CrossRef Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol. 2016;22:6876.CrossRef
25.
go back to reference Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;8:57–84.CrossRef Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;8:57–84.CrossRef
26.
go back to reference Tuorkey MJ. Cancer therapy with phytochemicals: present and future perspectives. Biomed Environ Sci. 2015;28:808–19.CrossRef Tuorkey MJ. Cancer therapy with phytochemicals: present and future perspectives. Biomed Environ Sci. 2015;28:808–19.CrossRef
27.
go back to reference González-Vallinas M, González-Castejón M, Rodríguez-Casado A, Ramírez de Molina A. Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutr Rev. 2013;71:585–99. González-Vallinas M, González-Castejón M, Rodríguez-Casado A, Ramírez de Molina A. Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutr Rev. 2013;71:585–99.
28.
go back to reference Tan BS, Kang O, Mai CW, Tiong KH, Khoo ASB, Pichika MR, Bradshaw TD, Leong CO. 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ). Cancer Lett. 2013;336:127–39.CrossRef Tan BS, Kang O, Mai CW, Tiong KH, Khoo ASB, Pichika MR, Bradshaw TD, Leong CO. 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ). Cancer Lett. 2013;336:127–39.CrossRef
29.
go back to reference Zhu Y, Warin RF, Soroka DN, Chen H, Sang S. Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: chemical synthesis and biological evaluation. PLoS One. 2013;8:e54677.CrossRef Zhu Y, Warin RF, Soroka DN, Chen H, Sang S. Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: chemical synthesis and biological evaluation. PLoS One. 2013;8:e54677.CrossRef
30.
go back to reference Johnson RC, Rogers P. 5-Fluorouracil as a selective agent for growth of leptospirae. J Bacteriol. 1964;87:422–6.CrossRef Johnson RC, Rogers P. 5-Fluorouracil as a selective agent for growth of leptospirae. J Bacteriol. 1964;87:422–6.CrossRef
31.
go back to reference Graham J, Muhsin M, Kirkpatrick P. Oxaliplatin. Nat Rev Drug Discov. 2004;3:11–2.CrossRef Graham J, Muhsin M, Kirkpatrick P. Oxaliplatin. Nat Rev Drug Discov. 2004;3:11–2.CrossRef
32.
go back to reference Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13:1841–51.CrossRef Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13:1841–51.CrossRef
33.
go back to reference Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol. 1990;181:195–213.CrossRef Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol. 1990;181:195–213.CrossRef
34.
go back to reference Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5:726.CrossRef Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5:726.CrossRef
35.
go back to reference Horsman MR, Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front Oncol. 2016;6:66.CrossRef Horsman MR, Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front Oncol. 2016;6:66.CrossRef
36.
go back to reference Schneider A, Younis RH, Gutkind JS. Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia. 2008;10:1295–302.CrossRef Schneider A, Younis RH, Gutkind JS. Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia. 2008;10:1295–302.CrossRef
37.
go back to reference Onozuka H, Tsuchihara K, Esumi H. Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. Cancer Sci. 2011;102:975–82.CrossRef Onozuka H, Tsuchihara K, Esumi H. Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. Cancer Sci. 2011;102:975–82.CrossRef
Metadata
Title
6-Shogaol enhances the anticancer effect of 5-fluorouracil, oxaliplatin, and irinotecan via increase of apoptosis and autophagy in colon cancer cells in hypoxic/aglycemic conditions
Authors
Marta Woźniak
Sebastian Makuch
Kinga Winograd
Jerzy Wiśniewski
Piotr Ziółkowski
Siddarth Agrawal
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-020-02913-8

Other articles of this Issue 1/2020

BMC Complementary Medicine and Therapies 1/2020 Go to the issue