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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Antitumor Potential of Berberine and Cinnamic Acid against Solid Ehrlich Carcinoma in Mice

Author(s): Rafa S. Almeer, Ahmed M. Aref, Romisa A. Hussein, Mohamed S. Othman and Ahmed E. Abdel Moneim*

Volume 19, Issue 3, 2019

Page: [356 - 364] Pages: 9

DOI: 10.2174/1871520618666181116162441

Price: $65

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Abstract

Background: Berberine and cinnamic acid are natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms.

Objective: In the present study, we aimed to investigate the proapoptotic potential of cinnamic acid and berberine in cancer cells by examining their effect on the expression of proapoptotic and antiapoptotic genes. Moreover, the effects of berberine and cinnamic acid on the antitumor activity of cisplatin were investigated in Ehrlich solid tumor-bearing mice.

Methods: For the study, 90 male mice were inoculated intramuscularly with Ehrlich ascites tumor cells (2.5 × 106/mouse), and then on day 4, mice were randomly divided into six experimental groups (group 1-untreated Ehrlich solid tumor (EST), group 2-EST treated CDDP, group 3-EST treated CA, group 4-EST treated BER, group 5-EST treated CA + CDDP, and group 6-EST treated BER + CDDP).

Results: The results showed that berberine and cinnamic acid significantly decreased tumor growth and tumor volume (-74.8 and -75.5%, respectively) both as single agents and in combination with cisplatin. Moreover, both berberine and cinnamic acid increased the ratio of tumor growth inhibition (-91.5 and -92.6%, respectively), mean survival time (61.5 and 26 days, respectively), and percentage increase in lifespan (559 and 263%, respectively) of the treated mice. Our results also showed that both berberine and cinnamic acid-induced apoptosis by increasing the Bax/Bcl-2 ratio (74.1 and 45.1, respectively) and caspase-3 expression (14.3- and 11.6-fold increase, respectively). Additionally, berberine and cinnamic acid decreased oxidative stress markers, as shown by the decrease in lipid peroxidation and nitric oxide levels and an increase in reduced glutathione level.

Conclusion: These results suggest that berberine and cinnamic acid have potential as antitumor and antioxidant agents derived from natural sources, which could be used alone or in combination with regular chemotherapeutic agents, such as cisplatin. These effects could be attributed to the proapoptotic activity of berberine and cinnamic acid.

Keywords: Berberine, cinnamic acid, ehrlich solid tumor, apoptosis, Bax/Bcl-2 ratio.

Graphical Abstract
[1]
Le, X.; Hanna, E.Y. Optimal regimen of cisplatin in squamous cell carcinoma of head and neck yet to be determined. Ann. Transl. Med., 2018, 6, 229.
[2]
WHO. Cancer, Fact sheet. Lyon: France 2017 [updated February 2017]; Available from:. http://www.who.int/mediacentre/factsheets/ fs297/en/
[3]
Ali, I.; Rahis, U.; Saleem, K.; Rather, A. Social aspects of cancer genesis. Cancer Ther., 2011, 8, 6-14.
[4]
Tan, W.; Lu, J.; Huang, M.; Li, Y.; Chen, M.; Wu, G.; Gong, J.; Zhong, Z.; Xu, Z.; Dang, Y.; Guo, J.; Chen, X.; Wang, Y. Anti-cancer natural products isolated from chinese medicinal herbs. Chin. Med., 2011, 6, 27.
[5]
Boulikas, T.; Vougiouka, M. Recent clinical trials using cisplatin, carboplatin and their combination chemotherapy drugs.(review) Oncol. Rep., 2004, 11, 559-595.
[6]
Ali, I.; Wani, W.A.; Saleem, K.; Haque, A. Platinum compounds: a hope for future cancer chemotherapy. Anticancer. Agents Med. Chem., 2013, 13, 296-306.
[7]
Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer, 2007, 7, 573-584.
[8]
Devarajan, P.; Tarabishi, R.; Mishra, J.; Ma, Q.; Kourvetaris, A.; Vougiouka, M.; Boulikas, T. Low renal toxicity of lipoplatin compared to cisplatin in animals. Anticancer Res., 2004, 24, 2193-2200.
[9]
Dasari, S.; Tchounwou, P.B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol., 2014, 740, 364-378.
[10]
Ali, P.I.; Saleem, R.K.; Haque, A.; El Azzouni, A. Natural products: Human friendly anti-cancer medications, Egypt Pharma. J., 2010, 9, 133-179.
[11]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod., 2012, 75, 311-335.
[12]
Voon, H.C.; Bhat, R.; Rusul, G. Flower extracts and their essential oils as potential antimicrobial agents for food uses and pharmaceutical applications. Compr. Rev. Food Sci. Food Saf., 2012, 11, 34-55.
[13]
Fernandez-Gil, B.I.; Guerra-Librero, A.; Shen, Y.Q.; Florido, Y.; Martínez-Ruiz, L.; García-López, S.; Adan, C.; Rodríguez-Santana, C.; Castroviejo, D.; Quiñones-Hinojosa, A.; Fernández-Martínez, J.; Abdel Moneim, A.E.; López, L.C.; Rodríguez-Ferrer, J.M. Escames, G. Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. Oxid. Med. Cell. Longev., 2019, 20197187128
[14]
Almeer, R.S.; Abdel Moneim, A.E. Evaluation of the protective effect of olive leaf extract on cisplatin-induced testicular damage in rats. Oxid. Med. Cell. Longev., 2018, 20188487248
[15]
Chen, X.W.; Di, Y.M.; Zhang, J.; Zhou, Z.W.; Li, C.G.; Zhou, S.F. Interaction of herbal compounds with biological targets: A case study with berberine. Sci. World J., 2012, 2012708292
[16]
Tillhon, M.; Ortiz, G.L.M.; Lombardi, P.; Scovassi, A.I. Berberine: New perspectives for old remedies. Biochem. Pharmacol., 2012, 84, 1260-1267.
[17]
Tang, Q.L.; Lai, M.L.; Zhong, Y.F.; Wang, A.M.; Su, J.K.; Zhang, M.Q. Antinociceptive effect of berberine on visceral hypersensitivity in rats. World J. Gastroenterol., 2013, 19, 4582-4589.
[18]
Zhang, M.; Wang, C.M.; Li, J.; Meng, Z.J.; Wei, S.N.; Li, J.; Bucala, R.; Li, Y.L.; Chen, L. Berberine protects against palmitate-induced endothelial dysfunction: Involvements of upregulation of AMPK and eNOS and downregulation of NOX4. Mediat Inflamm., 2013, 2013260464
[19]
Heidarian, E.; Rafieian-Kopaei, M.; Khoshdel, A.; Bakhshesh, M. Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet: An additional mechanism for the hypolipidemic effects of berberine. Asian Pac. J. Trop. Biomed., 2014, 4(Suppl. 1), S429-S435.
[20]
Choi, M.S.; Yuk, D.Y.; Oh, J.H.; Jung, H.Y.; Han, S.B.; Moon, D.C.; Hong, J.T. Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis. Anticancer Res., 2008, 28, 3777-3784.
[21]
Ho, Y.T.; Lu, C.C.; Yang, J.S.; Chiang, J.H.; Li, T.C.; Ip, S.W.; Hsia, T.C.; Liao, C.L.; Lin, J.G.; Wood, W.G.; Chung, J.G. Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells. Anticancer Res., 2009, 29, 4063-4070.
[22]
Hsu, W.H.; Hsieh, Y.S.; Kuo, H.C.; Teng, C.Y.; Huang, H.I.; Wang, C.J.; Yang, S.F.; Liou, Y.S.; Kuo, W.H. Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL. Arch. Toxicol., 2007, 81, 719-728.
[23]
Zhang, X.; Gu, L.; Li, J.; Shah, N.; He, J.; Yang, L.; Hu, Q.; Zhou, M. Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res., 2010, 70, 9895-9904.
[24]
Liu, Q.; Jiang, H.; Liu, Z.; Wang, Y.; Zhao, M.; Hao, C.; Feng, S.; Guo, H.; Xu, B.; Yang, Q.; Gong, Y. Berberine radiosensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51. PLoS One, 2011, 6e23427
[25]
Meeran, S.M.; Katiyar, S.; Katiyar, S.K. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicol. Appl. Pharmacol., 2008, 229, 33-43.
[26]
Pandey, M.K.; Sung, B.; Kunnumakkara, A.B.; Sethi, G.; Chaturvedi, M.M.; Aggarwal, B.B. Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res., 2008, 68, 5370-5379.
[27]
Katiyar, S.K.; Meeran, S.M.; Katiyar, N.; Akhtar, S. p53 Cooperates berberine-induced growth inhibition and apoptosis of non-small cell human lung cancer cells in vitro and tumor xenograft growth in vivo. Mol. Carcinog., 2009, 48, 24-37.
[28]
Hoskins, J.A. The occurrence, metabolism and toxicity of cinnamic acid and related compounds. J. Appl. Toxicol., 1984, 4, 283-292.
[29]
Zhang, L.P.; Ji, Z.Z. Synthesis, antiinflammatory and anticancer activity of cinnamic acids, their derivatives and analogues. Yao Xue Xue Bao, 1992, 27, 817-823.
[30]
Foti, M.C.; Daquino, C.; Geraci, C. Electron-transfer reaction of cinnamic acids and their methyl esters with the DPPH(*) radical in alcoholic solutions. J. Org. Chem., 2004, 69, 2309-2314.
[31]
Akao, Y.; Maruyama, H.; Matsumoto, K.; Ohguchi, K.; Nishizawa, K.; Sakamoto, T.; Araki, Y.; Mishima, S.; Nozawa, Y. Cell growth inhibitory effect of cinnamic acid derivatives from propolis on human tumor cell lines. Biol. Pharm. Bull., 2003, 26, 1057-1059.
[32]
Jaganathan, S.K.; Mondhe, D.; Wani, Z.A.; Pal, H.C.; Mandal, M. Effect of honey and eugenol on Ehrlich ascites and solid carcinoma. J. Biomed. Biotechnol., 2010, 2010989163
[33]
Loganayaki, N.; Manian, S. Antitumor activity of the methanolic extract of Ammannia baccifera L. against Dalton’s ascites lymphoma induced ascitic and solid tumors in mice. J. Ethnopharmacol., 2012, 142, 305-309.
[34]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95, 351-358.
[35]
Green, L.C.; Wagner, D.A.; Glogowski, J.; Skipper, P.L.; Wishnok, J.S.; Tannenbaum, S.R. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal. Biochem., 1982, 126, 131-138.
[36]
Sedlak, J.; Lindsay, R.H. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal. Biochem., 1968, 25, 192-205.
[37]
Safarzadeh, E.; Shotorbani, S.S.; Baradaran, B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv. Pharm. Bull., 2014, 4(Suppl. 1), 421-427.
[38]
Nabil, H.M.; Hassan, B.N.; Tohamy, A.A.; Waaer, H.F.; Abdel-Moneim, A.E. Radioprotection of 1,2-dimethylhydrazine-initiated colon cancer in rats using low-dose gamma rays by modulating multidrug resistance-1, cytokeratin 20, and beta-catenin expression. Hum. Exp. Toxicol., 2016, 35, 282-292.
[39]
El-Naa, M.M.; Othman, M.; Younes, S. Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis. Drug Des. Devel. Ther., 2016, 10, 3661-3672.
[40]
Wang, H.; Khor, T.O.; Shu, L.; Su, Z.Y.; Fuentes, F.; Lee, J.H.; Kong, A.N. Plants vs. cancer: A review on natural phytochemicals in preventing and treating cancers and their druggability. Anticancer. Agents Med. Chem., 2012, 12, 1281-1305.
[41]
Lindqvist, L.M.; Heinlein, M.; Huang, D.C.S.; Vaux, D.L. Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc. Natl. Acad. Sci. USA, 2014, 111, 8512-8517.
[42]
Patil, J.B.; Kim, J.; Jayaprakasha, G.K. Berberine induces apoptosis in breast cancer cells (MCF-7) through mitochondrial-dependent pathway. Eur. J. Pharmacol., 2010, 645, 70-78.
[43]
Kumar, A.; Chopra, E.K.; Mukherjee, M.; Pottabathini, R.; Dhull, D.K. Current knowledge and pharmacological profile of berberine: An update. Eur. J. Pharmacol., 2015, 761, 288-297.
[44]
Naveen, C.R.; Gaikwad, S.; Agrawal-Rajput, R. Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells. Phytomedicine, 2016, 23, 736-744.
[45]
Ayati, S.H.; Fazeli, B.; Momtazi-Borojeni, A.A.; Cicero, A.F.G.; Pirro, M.; Sahebkar, A. Regulatory effects of berberine on microRNome in Cancer and other conditions. Crit. Rev. Oncol. Hematol., 2017, 116, 147-158.
[46]
Wang, X.; Wang, N.; Li, H.; Liu, M.; Cao, F.; Yu, X.; Zhang, J.; Tan, Y.; Xiang, L.; Feng, Y. Up-Regulation of PAI-1 and Down-Regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. Int. J. Mol. Sci., 2016, 17, 577.
[47]
Inoue, K.; Kulsum, U.; Chowdhury, S.A.; Fujisawa, S.; Ishihara, M.; Yokoe, I.; Sakagami, H. Tumor-specific cytotoxicity and apoptosis-inducing activity of berberines. Anticancer Res., 2005, 25, 4053-4059.
[48]
Auyeung, K.K.; Ko, J.K. Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation. Int. J. Mol. Med., 2009, 24, 571-577.
[49]
Pereira, C.V.; Machado, N.G.; Oliveira, P.J. Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocator. Toxicol. Sci., 2008, 105, 408-417.
[50]
Ng, L.T.; Wu, S.J. Antiproliferative activity of cinnamomum cassia constituents and effects of pifithrin-alpha on their apoptotic signaling pathways in Hep G2 cells. Evid. Based Complement. Alternat. Med., 2011, 2011492148
[51]
Kwon, H.K.; Hwang, J.S.; So, J.S.; Lee, C.G.; Sahoo, A.; Ryu, J.H.; Jeon, W.K.; Ko, B.S.; Im, C.R.; Lee, S.H.; Park, Z.Y. Cinnamon extract induces tumor cell death through inhibition of NFkappaB and AP1. BMC Cancer, 2010, 10, 392.
[52]
Qi, G.; Chen, J.; Shi, C.; Wang, Y.; Mi, S.; Shao, W.; Yu, X.; Ma, Y.; Ling, J.; Huang, J. Cinnamic acid (CINN) induces apoptosis and proliferation in human nasopharyngeal carcinoma cells. Cell. Physiol. Biochem., 2016, 40, 589-596.
[53]
Choudhari, S.K.; Chaudhary, M.; Bagde, S.; Gadbail, A.R.; Joshi, V. Nitric oxide and cancer: A review. World J. Surg. Oncol., 2013, 11, 118.
[54]
Othman, M.S.; Safwat, G.; Aboulkhair, M.; Abdel Moneim, A.E. The potential effect of berberine in mercury-induced hepatorenal toxicity in albino rats. Food Chem. Toxicol., 2014, 69, 175-181.
[55]
Qian, G.Q.; Ding, J.; Zhang, X.; Yin, X.; Gao, Y.; Zhao, G.P. Preconditioning with glycyrrhizic, ferulic, paeoniflorin, cinnamic prevents rat hearts from ischemia/reperfusion injury via endothelial nitric oxide pathway. Pharmacogn. Mag., 2015, 11, 292-296.
[56]
Elkhateeb, W.A.; Zaghlol, G.M.; El-Garawani, I.M.; Ahmed, E.F.; Rateb, M.E.; Abdel-Moneim, A.E. Ganoderma applanatum secondary metabolites induced apoptosis through different pathways: In vivo and in vitro anticancer studies. Biomed. Pharmacother., 2018, 101, 264-277.
[57]
Alam, B.; Majumder, R.; Akter, S.; Lee, S.H. Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential. Oncol. Lett., 2015, 9, 863-868.
[58]
Pontiki, E.; Hadjipavlou-Litina, D.; Litinas, K.; Geromichalos, G. Novel cinnamic acid derivatives as antioxidant and anticancer agents: design, synthesis and modeling studies. Molecules, 2014, 19, 9655-9674.
[59]
De, P.; Baltas, M.; Bedos-Belval, F. Cinnamic acid derivatives as anticancer agents-a review. Curr. Med. Chem., 2011, 18, 1672-1703.
[60]
Pavić, K.; Perković, I.; Gilja, P.; Kozlina, F.; Ester, K.; Kralj, M.; Schols, D.; Hadjipavlou-Litina, D.; Pontiki, E.; Zorc, B. Design, synthesis and biological evaluation of novel primaquine-cinnamic acid conjugates of the amide and acylsemicarbazide type. Molecules, 2016, 28, 21.
[61]
Wondrak, G.T.; Villeneuve, N.F.; Lamore, S.D.; Bause, A.S.; Jiang, T.; Zhang, D.D. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules, 2010, 15, 3338-3355.
[62]
Solis, W.A.; Dalton, T.P.; Dieter, M.Z.; Freshwater, S.; Harrer, J.M.; He, L.; Shertzer, H.G.; Nebert, D.W. Glutamate-cysteine ligase modifier subunit: mouse Gclm gene structure and regulation by agents that cause oxidative stress. Biochem. Pharmacol., 2002, 63, 1739-1754.

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