Low Piperine Fractional Piper nigrum Extract Enhanced the Antitumor Immunity via Regulating the Th1/Th2/Treg Cell Subsets on NMU-Induced Tumorigenesis Rats

Abstract

Cancer is one of the major causes of death worldwide. In addition to standard regimens, tumor suppression ability has been demonstrated in many types of natural products, including Piper nigrum, or black pepper. In previous reports, we demonstrated the antitumor effect of low piperine fractional Piper nigrum extract in vitro and in vivo. However, the effects of low piperine fractional P. nigrum extract in the aspect of antitumor immunity has not yet been investigated. In this study, tumor-bearing rats were fed with 100 mg/kg BW or 200 mg/kg BW of low piperine fractional P. nigrum extract 3 times per week for 4 weeks. Tumor burden and hematological data were then evaluated. Immunological data was investigated using a cytokine array and flow cytometry. The results showed that both doses of low piperine fractional P. nigrum extract significantly suppressed tumor progression in N-nitrosomethylurea-induced mammary tumor rats. There were no significant changes observed in the total white blood cells, red blood cells, and hemoglobin. Low piperine fractional P. nigrum extract suppressed some cytokine and chemokine levels including CXCL7, sICAM-1, and L-selectin 0.2- to 0.6-fold. Interestingly, 200 mg/kg BW of low piperine fractional P. nigrum extract significantly promoted type 1 T helper cell, and suppressed neutrophil, basophil, type 2 T helper cell, and regulatory T cell compared to the control group. In summary, these results indicate that low piperine fractional P. nigrum extract had a high efficacy in supporting antitumor activity at immunological levels via regulating Th1/Th2/Treg cells.

Key words

Piperaceae - Piper nigrum - antitumor immunity - Th1 - Th2 - Treg - PFPE

Publication History

Received: 16 December 2020

Accepted after revision: 20 March 2021

Article published online:
26 April 2021

• References

• 1 Chatterjee S, Niaz Z, Gautam S, Adhikari S, Variyar P, Sharma A. Antioxidant activity of some phenolic constituents from green pepper (Piper nigrum L.) and fresh nutmeg mace (Myristica fragrans). Food Chem 2007; 101: 515-523
• 2 Morsy NFS, El-Salam EAA. Antimicrobial and antiproliferative activities of black pepper (Piper nigrum L.) essential oil and oleoresin. J Essent Oil Bear Plants 2017; 20: 779-790
• 3 Salehi B, Zakaria ZA, Gyawali R, Ibrahim SA, Rajkovic J, Shinwari ZK, Khan T, Sharifi-Rad J, Ozleyen A, Turkdonmez E, Valussi M, Tumer TB, Monzote Fidalgo L, Martorell M, Setzer WN. Piper species: A comprehensive review on their phytochemistry, biological activities and applications. Molecules 2019; 24: 1364
• 4 Butt MS, Pasha I, Sultan MT, Randhawa MA, Saeed F, Ahmed W. Black pepper and health claims: a comprehensive treatise. Crit Rev Food Sci Nutr 2013; 53: 875-886
• 5 Deng Y, Sriwiriyajan S, Tedasen A, Hiransai P, Graidist P. Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro . J Ethnopharmacol 2016; 188: 87-95
• 6 Prashant A, Rangaswamy C, Yadav AK, Reddy V, Sowmya MN, Madhunapantula S. In vitro anticancer activity of ethanolic extracts of Piper nigrum against colorectal carcinoma cell lines. Int J Appl Basic Med Res 2017; 7: 67-72
• 7 Xie Z, Wei Y, Xu J, Lei J, Yu J. Alkaloids from Piper nigrum synergistically enhanced the effect of paclitaxel against paclitaxel-resistant cervical cancer cells through the downregulation of Mcl-1. J Agric Food Chem 2019; 67: 5159-5168
• 8 Tasleem F, Azhar I, Ali SN, Perveen S, Mahmood ZA. Analgesic and anti-inflammatory activities of Piper nigrum L. Asian Pac J Trop Med 2014; 7S1: S461-S468
• 9 Dʼcruz SC, Mathur PP. Effect of piperine on the epididymis of adult male rats. Asian J Androl 2005; 7: 363-368
• 10 Allameh A, Saxena M, Biswas G, Raj HG, Singh J, Srivastava N. Piperine, a plant alkaloid of the piper species, enhances the bioavailability of aflatoxin B1 in rat tissues. Cancer Lett 1992; 61: 195-199
• 11 Teng MWL, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. J Clin Invest 2015; 125: 3338-3346
• 12 Zou JY, Su CH, Luo HH, Lei YY, Zeng B, Zhu HS, Chen ZG. Curcumin converts Foxp3+ regulatory T cells to T helper 1 cells in patients with lung cancer. J Cell Biochem 2018; 119: 1420-1428
• 13 Dandawate S, Williams L, Joshee N, Rimando AM, Mittal S, Thakur A, Lum LG, Parajuli P. Scutellaria extract and wogonin inhibit tumor-mediated induction of T(reg) cells via inhibition of TGF-β1 activity. Cancer Immunol Immunother 2012; 61: 701-711
• 14 Katiyar SK, Challa A, McCormick TS, Cooper KD, Mukhtar H. Prevention of UVB-induced immunosuppression in mice by the green tea polyphenol (−)-epigallocatechin-3-gallate may be associated with alterations in IL-10 and IL-12 production. Carcinogenesis 1999; 20: 2117-2124
• 15 Bui TT, Piao CH, Hyeon E, Fan Y, Van Nguyen T, Jung SY, Choi DW, Lee SY, Shin HS, Song CH, Chai OH. The protective role of Piper nigrum fruit extract in an ovalbumin-induced allergic rhinitis by targeting of NFκBp65 and STAT3 signalings. Biomed Pharmacother 2019; 109: 1915-1923
• 16 Bui TT, Piao CH, Song CH, Shin HS, Shon DH, Chai OH. Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation. Cell Immunol 2017; 322: 64-73
• 17 Majdalawieh AF, Carr RI. In vitro investigation of the potential immunomodulatory and anti-cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamomum). J Med Food 2010; 13: 371-381
• 18 Tedasen A, Dokduang S, Sukpondma Y, Lailerd N, Madla S, Sriwiriyajan S, Rattanaburee T, Tipmanee V, Graidist P. (−)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats. Eur J Pharmacol 2020; 882: 173311
• 19 Tedasen A, Khoka A, Madla S, Sriwiriyajan S, Graidist P. Anticancer effects of piperine-free Piper nigrum extract on cholangiocarcinoma cell lines. Pharmacogn Mag 2020; 16: 28
• 20 Sriwiriyajan S, Tedasen A, Lailerd N, Boonyaphiphat P, Nitiruangjarat A, Deng Y, Graidist P. Anticancer and cancer prevention effects of piperine-free Piper nigrum extract on N-nitrosomethylurea-induced mammary tumorigenesis in rats. Cancer Prev Res (Phila) 2016; 9: 74-82
• 21 Dahham SS, Tabana YM, Iqbal MA, Ahamed MB, Ezzat MO, Majid AS, Majid AM. The Anticancer, antioxidant and antimicrobial properties of the sesquiterpene β-caryophyllene from the essential oil of Aquilaria crassna . Molecules 2015; 20: 11808-11829
• 22 Basholli-Salihu M, Schuster R, Hajdari A, Mulla D, Viernstein H, Mustafa B, Mueller M. Phytochemical composition, anti-inflammatory activity and cytotoxic effects of essential oils from three Pinus spp. Pharm Biol 2017; 55: 1553-1560
• 23 Ngo QMT, Tran PT, Tran MH, Kim JA, Rho SS, Lim CH, Kim JC, Woo MH, Choi JS, Lee JH, Min BS. Alkaloids from Piper nigrum exhibit antiinflammatory activity via activating the Nrf2/HO-1 pathway. Phytother Res 2017; 31: 663-670
• 24 Chandra M, Prakash O, Kumar R, Bachheti RK, Bhushan B, Kumar M, Pant AK. β-selinene-rich essential oils from the parts of Callicarpa macrophylla and their antioxidant and pharmacological activities. Medicines (Basel) 2017; 4: 52
• 25 Chen JJ, Huang YC, Chen YC, Huang YT, Wang SW, Peng CY, Teng CM, Chen IS. Cytotoxic amides from Piper sintenense . Planta Med 2002; 68: 980-985
• 26 Fernandes ES, Passos GF, Medeiros R, da Cunha FM, Ferreira J, Campos MM, Pianowski LF, Calixto JB. Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea . Eur J Pharmacol 2007; 569: 228-236
• 27 Reynoso-Moreno I, Najar-Guerrero I, Escareño N, Flores-Soto ME, Gertsch J, Viveros-Paredes JM. An endocannabinoid uptake inhibitor from black pepper exerts pronounced anti-inflammatory effects in mice. J Agric Food Chem 2017; 65: 9435-9442
• 28 Sriwiriyajan S, Ninpesh T, Sukpondma Y, Nasomyon T, Graidist P. Cytotoxicity screening of plants of genus Piper in breast cancer cell lines. Trop J Pharm Res 2014; 13: 921
• 29 Ma C, Zhou W, Yan Z, Qu M, Bu X. β-Elemene treatment of glioblastoma: a single-center retrospective study. Onco Targets Ther 2016; 9: 7521-7526
• 30 Salehi B, Upadhyay S, Erdogan Orhan I, Kumar Jugran A, Jayaweera SL D, Dias DA, Sharopov F, Taheri Y, Martins N, Baghalpour N, Cho WC, Sharifi-Rad J. Therapeutic potential of α- and β-pinene: a miracle gift of nature. Biomolecules 2019; 9: 738
• 31 Yeo SK, Ali AY, Hayward OA, Turnham D, Jackson T, Bowen ID, Clarkson R. β-bisabolene, a sesquiterpene from the essential oil extract of opoponax (Commiphora guidottii), exhibits cytotoxicity in breast cancer cell lines. Phytother Res 2016; 30: 418-425
• 32 Rattanaburee T, Thongpanchang T, Wongma K, Tedasen A, Sukpondma Y, Graidist P. Anticancer activity of synthetic (±)-kusunokinin and its derivative (±)-bursehernin on human cancer cell lines. Biomed Pharmacother 2019; 117: 109115
• 33 de Souza Grinevicius VMA, Kviecinski MR, Santos Mota NSR, Ourique F, Porfirio Will Castro LS, Andreguetti RR, Gomes Correia JF, Filho DW, Pich CT, Pedrosa RC. 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: 139-147
• 34 Guan C, Liu W, Yue Y, Jin H, Wang X, Wang XJ. Inhibitory effect of β-elemene on human breast cancer cells. Int J Clin Exp Pathol 2014; 7: 3948-3956
• 35 Ee GC, Lim CM, Rahmani M, Shaari K, Bong CF. Pellitorine, a potential anti-cancer lead compound against HL60 and MCT-7 cell lines and microbial transformation of piperine from Piper nigrum . Molecules 2010; 15: 2398-2404
• 36 Chang YC, Hsu JD, Lin WL, Lee YJ, Wang CJ. High incidence of acute promyelocytic leukemia specifically induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Arch Toxicol 2012; 86: 315-327
• 37 Grépin R, Guyot M, Giuliano S, Boncompagni M, Ambrosetti D, Chamorey E, Scoazec JY, Negrier S, Simonnet H, Pagès G. The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma. Cancer Res 2014; 74: 873-883
• 38 von Hundelshausen P, Petersen F, Brandt E. Platelet-derived chemokines in vascular biology. Thromb Haemost 2007; 97: 704-713
• 39 Yamada M, Yanaba K, Takehara K, Sato S. Clinical significance of serum levels of soluble intercellular adhesion molecule-1 and soluble L-selectin in malignant melanoma. Arch Dermatol Res 2005; 297: 256-260
• 40 Schellerer VS, Langheinrich MC, Zver V, Grützmann R, Stürzl M, Gefeller O, Naschberger E, Merkel S. Soluble intercellular adhesion molecule-1 is a prognostic marker in colorectal carcinoma. Int J Colorectal Dis 2019; 34: 309-317
• 41 Tanaka S, Sakata Y, Morimoto K, Tambe Y, Watanabe Y, Honda G, Tabata M, Oshima T, Masuda T, Umezawa T, Shimada M, Nagakura N, Kamisako W, Kashiwada Y, Ikeshiro Y. Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules, ICAM-1 and VCAM-1. Planta Med 2001; 67: 108-113
• 42 Brostjan C, Oehler R. The role of neutrophil death in chronic inflammation and cancer. Cell Death Discov 2020; 6: 1-8
• 43 Rogerio AP, Andrade EL, Leite DF, Figueiredo CP, Calixto JB. Preventive and therapeutic anti-inflammatory properties of the sesquiterpene α-humulene in experimental airways allergic inflammation. Br J Pharmacol 2009; 158: 1074-1087
• 44 Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?. Cancer Sci 2019; 110: 2080-2089