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Piperine: role in prevention and progression of cancer

  • Mariia Zadorozhna
  • Tiziana Tataranni
  • Domenica MangieriEmail author
Review
  • 54 Downloads

Abstract

Cancer is among the leading causes of death worldwide. Several pharmacological protocols have been developed in order to block tumor progression often showing partial efficacy and severe counterproductive effects. It is now conceived that a healthy lifestyle coupled with the consumption of certain phytochemicals can play a protective role against tumor development and progression. According to this vision, it has been introduced the concept of “chemoprevention”. This term refers to natural agents with the capability to interfere with the tumorigenesis and metastasis, or at least, attenuate the cancer-related symptoms. Piperine (1-Piperoylpiperidine), a main extract of Piper longum and Piper nigrum, is an alkaloid with a long history of medicinal use. In fact, it exhibits a variety of biochemical and pharmaceutical properties, including chemopreventive activities without significant cytotoxic effects on normal cells, at least at doses < of 250 µg/ml. The aim of this review is to discuss the relevant molecular and cellular mechanisms underlying the chemopreventive action of this natural alkaloid.

Keywords

Piperine Chemoprevention Natural compounds Cancer therapy 

Abbreviations

AKT

Protein kinase B

CAM

Chick chorioallantoic membrane

CDKs

Cyclin-dependent kinases

CHOP

C/EBP homologous protein

CKIs

Cyclin-dependent inhibitors

CYPs

Cytochromes-P450

CSCs

Cancer stem cells

DNA

Desossiribonucleic acid

DMEs

Drugs metabolizing enzymes

DENA

Diethylnitrosamine

ECM

Extracellular matrix

EMT

Epithelial-mesenchymal transition

eNOS

Endothelial nitric oxide synthase

ER

Endoplasmic reticulum

ERK1/2

Extracellular-regulated kinase 1/2

FAs

Focal adhesions

GPX

Glutathione peroxidase

GR

Glutathione reductase

GRP78

Glucose-regulated protein 78

HUVECs

Human umbilical vein endothelial cells

HER2

Epidermal growth factor receptor-2

IGF

Insulin-like growth factor

IRE1a

Inositol-requiring enzyme-1-a

JNK

Jun N-terminal kinase

LC3II

Phosphatidylethanolamine conjugate 3II

MMPs

Matrix metalloproteinases

mTOR

Mammalian target of rapamycin

mTORCs

Mammalian target of rapamycin complexes

MAPK

Mitogen-activated protein kinase

NF-Kb

Nuclear factor-κB

Nox

Nicotinamide adenine dinucleotide phosphate oxidases

PARP

Poly-ADP ribose polymerase

PMA

Phorbol-12-myristate-13-acetate

PI3 K

Phosphoinositide-3 kinase

PKCα

Phospho-kinase C alpha

P-gp

P-glycoprotein

ROS

Reactive oxygen species

STAT-3

Signal transducer and activator of transcription-3

TGF-β

Trasformin growth factor-beta

TQ

Thymoquinone

UV

Ultraviolet

UDP-GDH

Uridine diphosphate -glucose dehydrogenase

UDP-GT

Uridine diphosphate-glucoronyl transferase

VEGF

Vascular endothelial growth factor/receptors

VEGFRs

VEGF receptors

XO

Xanthine oxidase

Notes

Author contributions

D.M. wrote and supervised manuscript; M.Z. assisted manuscript preparation. TT. facilitated the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest. All authors have read and approved the manuscript.

References

  1. 1.
    Gottesman MM, Pastan IH (2015) The role of multidrug resistance efflux pumps in cancer: revisiting a JNCI publication exploring expression of the MDR1 (P-glycoprotein) gene. J Natl Cancer Inst.  https://doi.org/10.1093/jnci/djv222 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Anand P, Kunnumakkara AB, Sundaram C et al (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116.  https://doi.org/10.1007/s11095-008-9661-9 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Parsa N (2012) Environmental factors inducing human cancers. Iran J Public Health 41:1–9PubMedPubMedCentralGoogle Scholar
  4. 4.
    Katzke VA, Kaaks R, Kuhn T (2015) Lifestyle and cancer risk. Cancer J 21:104–110.  https://doi.org/10.1097/PPO.0000000000000101 CrossRefPubMedGoogle Scholar
  5. 5.
    Hosseini A, Ghorbani A (2015) Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J Phytomed 5:84–97PubMedPubMedCentralGoogle Scholar
  6. 6.
    Zheng J, Zhou Y, Li Y et al (2016) Spices for prevention and treatment of cancers. Nutrients 8:495–530.  https://doi.org/10.3390/nu8080495 CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Lu JJ, Bao JL, Chen XP et al (2012) Alkaloids isolated from natural herbs as the anticancer agents. Evid Based Complement Altern Med.  https://doi.org/10.1155/2012/485042 CrossRefGoogle Scholar
  8. 8.
    Sunila ES, Kuttan G (2004) Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J Ethnopharmacol 90:339–346.  https://doi.org/10.1016/j.jep.2003.10.016 CrossRefPubMedGoogle Scholar
  9. 9.
    Kumar S, Kamboj J, Suman et al (2011) Overview for various aspects of the health benefits of Piper longum linn. fruit. J Acupunct Meridian Stud 4:134–140.  https://doi.org/10.1016/S2005-2901(11)60020-4 CrossRefPubMedGoogle Scholar
  10. 10.
    Paarakh PM, Sreeram DC (2015) In vitro cytotoxic and in silico activity of piperine isolated from Piper nigrum fruits Linn. Silico Pharmacol 3:9.  https://doi.org/10.1186/s40203-015-0013-2 CrossRefGoogle Scholar
  11. 11.
    Rodgers G, Doucette CD, Soutar DA et al (2016) Piperine impairs the migration and T cell-activating function of dendritic cells. Toxicol Lett 242:23–33.  https://doi.org/10.1016/j.toxlet.2015.11.025 CrossRefPubMedGoogle Scholar
  12. 12.
    Samuel M, Oliver SV, Coetzee M et al (2016) The larvicidal effects of black pepper (Piper nigrum L.) and piperine against insecticide resistant and susceptible strains of Anopheles malaria vector mosquitoes. Parasit Vectors 9:238–247.  https://doi.org/10.1186/s13071-016-1521-6 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sahi S, Tewatia P, Ghosal S (2012) Leishmania donovani pteridine reductase 1: comparative protein modeling and protein-ligand interaction studies of the leishmanicidal constituents isolated from the fruits of Piper longum. J Mol Model 18:5065–5073.  https://doi.org/10.1007/s00894-012-1508-y CrossRefPubMedGoogle Scholar
  14. 14.
    Philipova I, Valcheva V, Mihaylova R et al (2018) Synthetic piperine amide analogs with antimycobacterial activity. Chem Biol Drug Des 3:763–768.  https://doi.org/10.1111/cbdd.13140 CrossRefGoogle Scholar
  15. 15.
    Soutar DA, Doucette CD, Liwski RS et al (2017) Piperine, a pungent alkaloid from black pepper, inhibits B lymphocyte activation and effector functions. Phytother Res 31:466–474.  https://doi.org/10.1002/ptr.5772 CrossRefPubMedGoogle Scholar
  16. 16.
    Li C, Wang Z, Wang Q et al (2017) Enhanced anti-tumor efficacy and mechanisms associated with docetaxel-piperine combination- in vitro and in vivo investigation using a taxane-resistant prostate cancer model. Oncotarget 9(3):3338–3352.  https://doi.org/10.18632/oncotarget.23235 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Manayi A, Nabavi SM, Setzer WN et al (2017) Piperine as a potential anti-cancer agent: a review on preclinical studies. Curr Med Chem.  https://doi.org/10.2174/0929867324666170523120656 CrossRefGoogle Scholar
  18. 18.
    Meeran SM, Katiyar SK (2008) Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci 13:2191–2202CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vermeulen K, Berneman ZN, Van Bockstaele DR (2003) Cell cycle and apoptosis. Cell Prolif 36:165–175CrossRefPubMedGoogle Scholar
  20. 20.
    Feitelson MA, Arzumanyan A, Kulathinal RJ et al (2015) Sustained proliferation in cancer: mechanisms and novel therapeutic targets. Semin Cancer Biol 35(Suppl):25–54.  https://doi.org/10.1016/j.semcancer.2015.02.006 CrossRefGoogle Scholar
  21. 21.
    Siddiqui S, Ahamad MS, Jafri A et al (2017) Piperine triggers apoptosis of human oral squamous carcinoma through cell cycle arrest and mitochondrial oxidative stress. Nutr Cancer 69:791–799.  https://doi.org/10.1080/01635581.2017.1310260 CrossRefPubMedGoogle Scholar
  22. 22.
    Fofaria NM, Kim SH, Srivastava SK (2014) Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation. PLoS ONE.  https://doi.org/10.1371/journal.pone.0094298 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yaffe PB, Power Coombs MR, Doucette CD et al (2015) Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress. Mol Carcinog 54:1070–1085.  https://doi.org/10.1002/mc.22176 CrossRefPubMedGoogle Scholar
  24. 24.
    Ouyang DY, Zeng LH, Pan H et al (2013) Piperine inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and autophagy. Food Chem Toxicol 60:424–430.  https://doi.org/10.1016/j.fct.2013.08.007 CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang J, Zhu X, Li H et al (2015) Piperine inhibits proliferation of human osteosarcoma cells viaG2/M phase arrest and metastasis by suppressing MMP-2/-9 expression. Int Immunopharmacol 24:50–58.  https://doi.org/10.1016/j.intimp.2014.11.012 CrossRefPubMedGoogle Scholar
  26. 26.
    Lai LH, Fu QH, Liu Y et al (2012) Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 murine breast cancer model. Acta Pharmacol Sin 33:523–530.  https://doi.org/10.1038/aps.2011.209 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jain S, Meka SRK, Chatterjee K (2016) Engineering a piperine eluting nanofibrous patch for cancer treatment. ACS Biomater Sci Eng 2:1376–1385.  https://doi.org/10.1021/acsbiomaterials.6b00297 CrossRefGoogle Scholar
  28. 28.
    Greenshields AL, Doucette CD, Sutton KM et al (2015) Piperine inhibits the growth and motility of triple-negative breast cancer cells. Cancer Lett 357:129–140.  https://doi.org/10.1016/j.canlet.2014.11.017 CrossRefPubMedGoogle Scholar
  29. 29.
    Wei H, Wei S, Gan B et al (2011) Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 25:1510–1527.  https://doi.org/10.1101/gad.2051011 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lum JJ, Bauer DE, Kong M et al (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120:237–248.  https://doi.org/10.1016/j.cell.2004.11.046 CrossRefPubMedGoogle Scholar
  31. 31.
    Ogata M, Hino S, Saito A et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231.  https://doi.org/10.1128/MCB.01453-06 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Scherz-Shouval R, Shvets E, Fass E et al (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760.  https://doi.org/10.1038/sj.emboj.7601623 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Saha S, Panigrahi DP, Patil S et al (2018) Autophagy in health and disease: a comprehensive review. Biomed Pharmacother 104:485–495.  https://doi.org/10.1016/j.biopha.2018.05.007 CrossRefPubMedGoogle Scholar
  34. 34.
    Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:651–662.  https://doi.org/10.1056/NEJMc1303158 CrossRefPubMedGoogle Scholar
  35. 35.
    White E, Mehnert JM (2015) Autophagy, metabolism, and cancer. Clin Cancer Res 21:5037–5046.  https://doi.org/10.1101/sqb.2016.81.030981 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sharifi MN, Mowers EE, Drake LE et al (2016) Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep 15:1660–1672.  https://doi.org/10.1016/j.celrep.2016.04.065 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen N, Karantza-Wadsworth V (2009) Role and regulation of autophagy in cancer. Biochim Biophys Acta 1793:1516–1523.  https://doi.org/10.1016/j.bbamcr.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Degenhardt K, Mathew R, Beaudoin B et al (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10:51–64.  https://doi.org/10.1016/j.ccr.2006.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lin SR, Fu YS, Tsai MJ (2017) Natural compounds from herbs that can potentially execute as autophagy inducers for cancer therapy. Int J Mol Sci.  https://doi.org/10.3390/ijms18071412 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Foster KG, Acosta-Jaquez HA, Romeo Y et al (2010) Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. J Biol Chem 285:80–94.  https://doi.org/10.1074/jbc.M109.029637 CrossRefPubMedGoogle Scholar
  41. 41.
    Moreau R, Kaur H (2017) Curcumin and piperine inhibit mTORC1 signaling in intestinal epithelial cells. FASEB J 31(Suppl 1):135–138Google Scholar
  42. 42.
    Tanaka T (2013) Role of apoptosis in the chemoprevention of cancer. J Exp Clin Med 5:89–91.  https://doi.org/10.4236/jbpc.2012.32018 CrossRefGoogle Scholar
  43. 43.
    Samykutty A, Shetty AV, Dakshinamoorthy G et al (2013) Piperine, a bioactive component of pepper spice exerts therapeutic effects on androgen dependent and androgen independent prostate cancer cells. PLoS ONE.  https://doi.org/10.1371/journal.pone.0065889 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Si L, Yang R, Lin R et al (2018) Piperine functions as a tumor suppressor for human ovarian tumor growth via activation of JNK/p38 MAPK-mediated intrinsic apoptotic pathway. Biosci Rep 1:1.  https://doi.org/10.1042/BSR20180503 CrossRefGoogle Scholar
  45. 45.
    Bukhari IA, Pivac N, Alhumayyd MS et al (2013) The analgesic and anticonvulsant effects of piperine in mice. J Physiol Pharmacol 64(6):789–794PubMedGoogle Scholar
  46. 46.
    Taqvi SI, Shah AJ, Gilani AH (2008) Blood pressure lowering and vasomodulator effects of piperine. J Cardiovasc Pharmacol 52:452–458.  https://doi.org/10.1097/FJC.0b013e31818d07c0 CrossRefPubMedGoogle Scholar
  47. 47.
    Ononiwu IM, Ibeneme CE, Ebong OO (2002) Effects of piperine on gastric acid secretion in albino rats. Afr J Med Med Sci 31:293–305PubMedGoogle Scholar
  48. 48.
    Sharma RA, Harris AL, Dalgleish AG et al (2001) Angiogenesis as a biomarker and target in cancer chemoprevention. Lancet Oncol 2:726–732.  https://doi.org/10.1016/S1470-2045(01)00586-1 CrossRefPubMedGoogle Scholar
  49. 49.
    Doucette CD, Hilchie AL, Liwski R et al (2013) Piperine, a dietary phytochemical, inhibits angiogenesis. J Nutr Biochem 24:231–239.  https://doi.org/10.1016/j.jnutbio.2012.05.009 CrossRefPubMedGoogle Scholar
  50. 50.
    Sunila ES, Kuttan G (2006) Piper longum inhibits VEGF and proinflammatory cytokines and tumor-induced angiogenesis in C57BL/6 mice. Int Immunopharmacol 6:733–741.  https://doi.org/10.1016/j.intimp.2005.10.013 CrossRefPubMedGoogle Scholar
  51. 51.
    Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci.  https://doi.org/10.3389/fnmol.2011.00051 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Poleszczuk J, Hahnfeldt P, Enderling H (2015) Therapeutic implications from sensitivity analysis of tumor angiogenesis models. PLoS ONE.  https://doi.org/10.1371/journal.pone.0120007 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Siddiqui S, White MW, Schroeder AM et al (2018) Aberrant DNMT3B7 expression correlates to tissue type, stage, and survival across cancers. PLoS ONE.  https://doi.org/10.1371/journal.pone.0201522 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    John A, Tuszynski G (2001) The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 7:14–23CrossRefPubMedGoogle Scholar
  55. 55.
    Kajanne R, Miettinen P, Mehlem A et al (2007) EGF-R regulates MMP function in fibroblasts through MAPK and AP-1 pathways. J Cell Physiol 212:489–497.  https://doi.org/10.1002/jcp.21041 CrossRefPubMedGoogle Scholar
  56. 56.
    Hwang YP, Yun HJ, Kim HG et al (2011) Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCalpha/ERK1/2- dependent matrix metalloproteinase-9 expression. Toxicol Lett 203:9–19.  https://doi.org/10.1016/j.toxlet.2011.02.013 CrossRefPubMedGoogle Scholar
  57. 57.
    Do MT, Kim HG, Choi JH et al (2013) Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells. Food Chem 141:2591–2599.  https://doi.org/10.1016/j.foodchem.2013.04.125 CrossRefPubMedGoogle Scholar
  58. 58.
    Grivennikova VG, Vladimir S, Kozlovsky VS et al (2017) Respiratory complex II: ROS production and the kinetics of ubiquinone reduction. Biochim Biophys Acta 1858:109–117.  https://doi.org/10.1016/j.bbabio.2016.10.008 CrossRefGoogle Scholar
  59. 59.
    Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95.  https://doi.org/10.1152/physrev.00018.2001 CrossRefPubMedGoogle Scholar
  60. 60.
    Bachi A, Dalle-Donne I, Scaloni A (2013) Redox proteomics: chemical principles, methodological approaches and biological/biomedical promises. Chem Rev 113:596–698.  https://doi.org/10.1021/cr300073p CrossRefPubMedGoogle Scholar
  61. 61.
    Galadari S, Rahman A, Pallichankandy S et al (2017) Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med 104:144–164.  https://doi.org/10.1016/j.freeradbiomed.2017.01.004 CrossRefPubMedGoogle Scholar
  62. 62.
    Di Meo S, Reed TT, Venditti P et al (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev.  https://doi.org/10.1155/2016/1245049 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    D’Autréaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824.  https://doi.org/10.1038/nrm2256 CrossRefPubMedGoogle Scholar
  64. 64.
    Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44:479–496.  https://doi.org/10.3109/10715761003667554 CrossRefPubMedGoogle Scholar
  65. 65.
    Hu Y, Zhao C, Zheng H et al (2017) A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs 28:392–400.  https://doi.org/10.1097/CAD.0000000000000470 CrossRefPubMedGoogle Scholar
  66. 66.
    Panieri E, Santoro MM (2016) ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis.  https://doi.org/10.1038/cddis.2016.105 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Kim J, Kim J, Bae JS (2016) ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 1:1.  https://doi.org/10.1038/emm.2016.119 CrossRefGoogle Scholar
  68. 68.
    Mittal R, Gupta RL (2000) In vitro antioxidant activity of piperine. Methods Find Exp Clin Pharmacol 22:271–274CrossRefPubMedGoogle Scholar
  69. 69.
    Damanhouri ZA, Ahmad A (2014) A review on therapeutic potential of Piper nigrum L. black pepper: the king of spices. Med Aromat Plants.  https://doi.org/10.4172/2167-0412.1000161 CrossRefGoogle Scholar
  70. 70.
    Srinivasan K (2007) Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 47:735–748.  https://doi.org/10.1080/10408390601062054 CrossRefPubMedGoogle Scholar
  71. 71.
    Kumari S, Badana AK, Malla R (2018) Reactive oxygen species: a key constituent in cancer survival. Biomark Insights 1:1.  https://doi.org/10.1177/1177271918755391 CrossRefGoogle Scholar
  72. 72.
    Zhou D, Shao L, Spitz DR (2014) Reactive oxygen species in normal and tumor stem cells. Adv Cancer Res 122:1–67.  https://doi.org/10.1016/B978-0-12-420117-0.00001-3 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Cairns RA, Harris I, McCracken S et al (2011) Cancer cell metabolism. Cold Spring Harb Symp Quant Biol 76:299–311.  https://doi.org/10.1101/sqb.2011.76.012856 CrossRefPubMedGoogle Scholar
  74. 74.
    Valko M, Izakovic M, Mazur M et al (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56CrossRefPubMedGoogle Scholar
  75. 75.
    Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal histological functions and human disease. Int J Biochem Cell Biol 39:44–84.  https://doi.org/10.1016/j.biocel.2006.07.001 CrossRefPubMedGoogle Scholar
  76. 76.
    Selvendiran K, Banu SM, Sakthisekaran D (2004) Protective effect of piperine on benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Clin Chim Acta 350:73–78.  https://doi.org/10.1016/j.cccn.2004.07.004 CrossRefPubMedGoogle Scholar
  77. 77.
    Selvendiran K, Prince Vijeya Singh J, Sakthisekaran D (2006) In vivo effect of piperine on serum and tissue glycoprotein levels in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Pulm Pharmacol Ther 19:107–111.  https://doi.org/10.1016/j.pupt.2005.04.002 CrossRefPubMedGoogle Scholar
  78. 78.
    Khajuria A, Thusu N, Zutshi U et al (1998) Piperine modulation of carcinogen induced oxidative stress in intestinal mucosa. Mol Cell Biochem 189:113–118CrossRefPubMedGoogle Scholar
  79. 79.
    Wondrak GT (2009) Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid Redox Signal 11:3013–3069.  https://doi.org/10.1089/ARS.2009.2541 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Gunasekaran V, Elangovan K, Niranjali Devaraj S (2017) Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: an in vitro and in vivo study. Food Chem Toxicol 105:106–118.  https://doi.org/10.1016/j.fct.2017.03.029 CrossRefPubMedGoogle Scholar
  81. 81.
    Yaffe PB, Doucette CD, Walsh M (2013) Piperine impairs cell cycle progression and causes reactive oxygen species dependent apoptosis in rectal cancer cells. Exp Mol Pathol 94:109–114.  https://doi.org/10.1016/j.yexmp.2012.10.008 CrossRefPubMedGoogle Scholar
  82. 82.
    Martin-Cordero C, Leon-Gonzalez AJ, Calderon-Montano JM et al (2012) Pro-oxidant natural products as anticancer agents. Curr Drug Targets 13:1006–1028CrossRefPubMedGoogle Scholar
  83. 83.
    Lee W, Kim KY, Yu SN et al (2013) Pipernonaline from Piper longum Linn. induces ROS-mediated apoptosis in human prostate cancer PC-3 cells. Biochem Biophys Res Commun 430:406–412.  https://doi.org/10.1016/j.bbrc.2012.11.030 CrossRefPubMedGoogle Scholar
  84. 84.
    Aponte PM, Caicedo A (2017) Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int 1:1.  https://doi.org/10.1155/2017/5619472 CrossRefGoogle Scholar
  85. 85.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674.  https://doi.org/10.1016/j.cell.2011.02.013 CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Liu Q, Mao H, Nie J et al (2008) Transforming growth factor {beta}1 induces epithelial-mesenchymal transition by activating the JNK-Smad3 pathway in rat peritoneal mesothelial cells. Perit Dial Int 28(Suppl 3):88–95Google Scholar
  87. 87.
    Carnero A, Garcia-Mayea Y, Mir C et al (2016) The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev 49:25–36.  https://doi.org/10.1016/j.ctrv.2016.07.001 CrossRefPubMedGoogle Scholar
  88. 88.
    Safa AR (2016) Resistance to cell death and its modulation in cancer stem cells. Crit Rev Oncog 21:203–219.  https://doi.org/10.1615/CritRevOncog.2016016976 CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Zang S, Liu T, Shi J (2014) Curcumin: a promising agent targeting cancer stem cells. Anticancer Agents Med Chem 14:787–792CrossRefPubMedGoogle Scholar
  90. 90.
    Chung SS, Vadgama JV (2015) Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of STAT3-NFκB signaling. Anticancer Res 35(1):39–46PubMedPubMedCentralGoogle Scholar
  91. 91.
    Kim DY, Kim EJ, Jang WG (2018) Piperine induces osteoblast differentiation through AMPK-dependent Runx2 expression. Biochem Biophys Res Commun 495(1):1497–1502.  https://doi.org/10.1016/j.bbrc.2017.11.200 CrossRefPubMedGoogle Scholar
  92. 92.
    Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13(14):4042–4045.  https://doi.org/10.1158/1078-0432.CCR-06-2316 CrossRefPubMedGoogle Scholar
  93. 93.
    Haegebarth A, van der Flier LG, van Gijn ME et al (2009) Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136:903–912.  https://doi.org/10.1016/j.cell.2009.01.031 CrossRefPubMedGoogle Scholar
  94. 94.
    Wang J, Wang C, Meng Q et al (2012) siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth. Mol Biol Rep 39:2497–2503.  https://doi.org/10.1007/s11033-011-1001-1 CrossRefPubMedGoogle Scholar
  95. 95.
    Kakarala M, Brenner DE, Khorkaya H et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122:777–785.  https://doi.org/10.1007/s10549-009-0612-x CrossRefPubMedGoogle Scholar
  96. 96.
    Tarapore RS, Siddiqui IA, Mukhtar H (2012) Modulation of Wnt/β-catenin signaling pathway by bioactive food components. Carcinogenesis 33(3):483–491.  https://doi.org/10.1093/carcin/bgr305 CrossRefPubMedGoogle Scholar
  97. 97.
    Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95.  https://doi.org/10.1186/bcr1021 CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Huang J, Li H, Ren G (2015) Epithelial-mesenchymal transition and drug resistance in breast cancer (Review). Int J Oncol 47:840–848.  https://doi.org/10.3892/ijo.2015.3084 CrossRefPubMedGoogle Scholar
  99. 99.
    Zhou P, Zhang R, Wang Y et al (2017) Cepharanthine hydrochloride reverses the mdr1 (P-glycoprotein)-mediated esophageal squamous cell carcinoma cell cisplatin resistance through JNK and p53 signals. Oncotarget 8:111144–111160.  https://doi.org/10.18632/oncotarget.22676 CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE et al (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485.  https://doi.org/10.1038/sj.onc.1206948 CrossRefPubMedGoogle Scholar
  101. 101.
    Callaghan R, Luk F, Bebawy M (2014) Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy? Drug Metab Dispos 42:623–631.  https://doi.org/10.1124/dmd.113.056176 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Syed SB, Arya H, Fu IH et al (2017) Targeting P-glycoprotein: investigation of piperine analogs for overcoming drug resistance in cancer. Sci Rep.  https://doi.org/10.1038/s41598-017-08062-2 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Fisher MB, Henne KR, Boer J (2006) The complexities inherent in attempts to decrease drug clearance by blocking sites of CYP-mediated metabolism. Curr Opin Drug Discov Devel 9:101–109PubMedGoogle Scholar
  104. 104.
    Makhov P, Golovine K, Canter D et al (2012) Co-administration of piperine and docetaxel results in improved anti-tumor efficacy via inhibition of CYP3A4 activity. Prostate 72:661–677.  https://doi.org/10.1002/pros.21469 CrossRefPubMedGoogle Scholar
  105. 105.
    Najar IA, Sharma SC, Singh GD et al (2011) Involvement of P-glycoprotein and CYP 3A4 in the enhancement of etoposide bioavailability by a piperine analogue. Chem Biol Interact 190:84–90.  https://doi.org/10.1016/j.cbi.2011.02.011 CrossRefPubMedGoogle Scholar
  106. 106.
    Katiyar SS, Muntimadugu E, Rafeeqi TA et al (2016) Co-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatment. Drug Deliv 23:2608–2616.  https://doi.org/10.3109/10717544.2015.1039667 CrossRefPubMedGoogle Scholar
  107. 107.
    Reen RK, Roesch SF, Kiefer F et al (1996) Piperine impairs cytochrome P4501A1 activity by direct interaction with the enzyme and not by down regulation of CYP1A1 gene expression in the rat hepatoma 5L cell line. Biochem Biophys Res Commun 218:562–569.  https://doi.org/10.1006/bbrc.1996.0100 CrossRefPubMedGoogle Scholar
  108. 108.
    Atal N, Bedi KL (2010) Bioenhancers: revolutionary concept to market. J Ayurveda Integr Med 1:96–99.  https://doi.org/10.4103/0975-9476.65073 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Selvendiran K, Thirunavukkarasu C, Singh JP et al (2005) Chemopreventive effect of piperine on mitochondrial TCA cycle and phase-I and glutathione-metabolizing enzymes in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Mol Cell Biochem 271:101–106CrossRefPubMedGoogle Scholar
  110. 110.
    Jobin C, Bradham CA, Russo MP et al (1999) Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 163:3474–3483PubMedGoogle Scholar
  111. 111.
    Park MJ, Kim EH, Park IC et al (2002) Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitor, p21WAF1/CIP1, p27KIP1 and p53. Int J Oncol 21:379–383PubMedGoogle Scholar
  112. 112.
    Aoki H, Takada Y, Kondo S et al (2007) Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72:29–39.  https://doi.org/10.1124/mol.106.033167 CrossRefPubMedGoogle Scholar
  113. 113.
    Shinojima N, Yokoyama T, Kondo Y et al (2007) Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3:635–637CrossRefPubMedGoogle Scholar
  114. 114.
    Yoysungnoen P, Wirachwong P, Bhattarakosol P et al (2006) Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc 34:109–115PubMedGoogle Scholar
  115. 115.
    Hogg SJ, Chitcholtan K, Hassan W et al (2015) Resveratrol, acetyl-resveratrol, and polydatin exhibit antigrowth activity against 3D cell aggregates of the SKOV-3 and OVCAR-8 ovarian cancer cell lines. Obstet Gynecol Int 2015:279591.  https://doi.org/10.1155/2015/27959 CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Mikuła-Pietrasik J, Sosińska P, Murias M et al (2015) High potency of a novel resveratrol derivative, 3,3′,4,4′-Tetrahydroxy-trans-stilbene, against ovarian cancer is associated with an oxidative stress-mediated imbalance between DNA damage accumulation and repair. Oxid Med Cell Longev 2015:135691.  https://doi.org/10.1155/2015/135691 CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Ahmad N, Adhami VM, Afaq F et al (2001) Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin Cancer Res 7:1466–1473PubMedGoogle Scholar
  118. 118.
    Kuo PL, Chiang LC, Lin CC (2002) Resveratrol-induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells. Life Sci 72:23–34.  https://doi.org/10.1016/S0024-3205(02)02177-X CrossRefPubMedGoogle Scholar
  119. 119.
    Liao PC, Ng LT, Lin LT et al (2010) Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. J Med Food 13:1415–1423.  https://doi.org/10.1089/jmf.2010.1126 CrossRefPubMedGoogle Scholar
  120. 120.
    Li W, Ma J, Ma Q et al (2013) Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3 K/Akt/NF-κB pathway. Curr Med Chem 20:4185–4194.  https://doi.org/10.2174/09298673113209990251 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Zhong LX, Li H, Wu ML et al (2015) Inhibition of STAT3 signaling as critical molecular event in resveratrol-suppressed ovarian cancer cells. J Ovarian Res 8:25.  https://doi.org/10.1186/s13048-015-0152-4 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Shankar S, Chen Q, Siddiqui I et al (2007) Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4′, 5 tri-hydroxystilbene): molecular mechanisms and therapeutic potential. J Mol Signal 2:7.  https://doi.org/10.1186/1750-2187-2-7 CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Shankar S, Siddiqui I, Srivastava RK (2007) Molecular mechanisms of resveratrol (3,4,5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. Mol Cell Biochem 304:273–285.  https://doi.org/10.1007/s11010-007-9510-x CrossRefPubMedGoogle Scholar
  124. 124.
    Gali-Muhtasib HU, Kheir WGA, Kheir LA et al (2004) Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. Anticancer Drugs 15:389–399CrossRefPubMedGoogle Scholar
  125. 125.
    Salim LZA, Othman R, Abdulla MA et al (2014) Thymoquinone inhibits murine leukemia WEHI-3 cells in vivo and in vitro. PLoS ONE 9:e115340.  https://doi.org/10.1371/journal.pone.0120034 CrossRefPubMedGoogle Scholar
  126. 126.
    Ashour AE, Abd-Allah AR, Korashy HM et al (2014) Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis. Mol Cell Biochem 389:85–98.  https://doi.org/10.1007/s11010-013-1930-1 CrossRefPubMedGoogle Scholar
  127. 127.
    Rajput S, Kumar BP, Dey KK et al (2013) Molecular targeting of Akt by thymoquinone promotes G1 arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells. Life Sci 93:783–790.  https://doi.org/10.1016/j.lfs.2013.09.009 CrossRefPubMedGoogle Scholar
  128. 128.
    Chen MC, Lee NH, Hsu HH et al (2015) Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38. J Agric Food Chem 63:1540–1546.  https://doi.org/10.1021/jf5054063 CrossRefPubMedGoogle Scholar
  129. 129.
    Peng L, Liu A, Shen Y et al (2013) Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-kB pathway. Oncol Rep 29:571–578.  https://doi.org/10.3892/or.2012.2165 CrossRefPubMedGoogle Scholar
  130. 130.
    Khan MA, Tania M, Wei C et al (2015) Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition. Oncotarget 6:19580–19591.  https://doi.org/10.18632/oncotarget.3973 CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Li F, Rajendran P, Sethi G (2010) Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br J Pharmacol 161:541–554CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Patial VSM, Sharma S, Pratap K (2015) Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol 40:445–452.  https://doi.org/10.1016/j.etap.2015.07.012 CrossRefPubMedGoogle Scholar
  133. 133.
    Johnson JJ, Nihal M, Siddiqui IA et al (2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res 55:1169–1176.  https://doi.org/10.1002/mnfr.201100117 CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Tephly TR, Burchell B (1990) UDP-glucuronosyltransferases: a family of detoxifying enzymes. Trends Pharmacol Sci 11:276–279CrossRefPubMedGoogle Scholar
  135. 135.
    Peng L, Liu A, Shen Y et al (2013) Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep 2:571–578.  https://doi.org/10.3892/or.2012.2165 CrossRefGoogle Scholar
  136. 136.
    Khader M, Eckl PM (2014) Thymoquinone: an emerging natural drug with a wide range of medical applications. Iran J Basic Med Sci 17:950–957PubMedPubMedCentralGoogle Scholar
  137. 137.
    Talib WH (2017) Regressing of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci Pharm.  https://doi.org/10.3390/scipharm85030027 CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Gorgani L, Mohammadi M, Najafpour GD et al (2017) Piperine—the bioactive compound of black pepper: from isolation to medicinal formulations. Compr Rev Food Sci Food Saf 16:124–140.  https://doi.org/10.1111/1541-4337.12246 CrossRefGoogle Scholar
  139. 139.
    Agrawal OP (2010) Organic chemistry natural products, 38th edn, vol II. Satyendra Rastogi “Mitra”, Meerut, IndiaGoogle Scholar
  140. 140.
    Bhat BG, Chandrasekhara N (1986) Studies on the metabolism of piperine: absorption, tissue distribution and excretion of urinary conjugates in rats. Toxicology 40:83–92CrossRefPubMedGoogle Scholar
  141. 141.
    Wadhawa S, Singhal S, Rawat S (2014) Bioavailability enhancement by piperine: a review. Asian J Biomed Pharm Sci 4:1–8.  https://doi.org/10.15272/ajbps.v4i36.576 CrossRefGoogle Scholar
  142. 142.
    Bajad S, Singla AK, Bedi KL (2002) Liquid chromatographic method for determination of piperine in rat plasma: application to pharmacokinetics. J Chromatogr B Analyt Technol Biomed Life Sci 776:245–249CrossRefPubMedGoogle Scholar
  143. 143.
    Suresh D, Srinivasan K (2010) Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J Med Res 131:682–691PubMedGoogle Scholar
  144. 144.
    Vasavirama K, Upender M (2014) Piperine: a valuable alkaloid from piper species. Int J Sci 6:34–38Google Scholar
  145. 145.
    Izgelov D, Cherniakov I, Aldouby Bier G et al (2018) The effect of piperine pro-nano lipospheres on direct intestinal phase II metabolism: the raloxifene paradigm of enhanced oral bioavailability. Mol Pharm 15:1548–1555.  https://doi.org/10.1021/acs.molpharmaceut.7b01090 CrossRefPubMedGoogle Scholar
  146. 146.
    Ashour EA, Majumdar S, Alsheteli A et al (2016) Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine. J Pharm Pharmacol 68:989–998.  https://doi.org/10.1111/jphp.12579 CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Zafar F, Jahan N, Khalil-Ur-Rahman et al (2019) Increased oral bioavailability of piperine from an optimized piper nigrum nanosuspension. Planta Med 85:249–257.  https://doi.org/10.1055/a-0759-2208 CrossRefPubMedGoogle Scholar
  148. 148.
    Shao B, Cui C, Ji H et al (2015) Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro, in vivo and in situ intestinal permeability studies. Drug Deliv 22:740–747.  https://doi.org/10.3109/10717544.2014.898109 CrossRefPubMedGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Medical and Surgical SciencesUniversity of FoggiaFoggiaItaly
  2. 2.Laboratory of Pre-Clinical and Translational ResearchIRCCS-CROB, Referral Cancer Center of BasilicataRionero in VultureItaly

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