Review on Anticancer properties of Piperine in Oral cancer: Therapeutic Perspectives

 

Vidhya Rekha U1, Prabhu MN2, Bhuminathan. S3

1Reader, Department of Public Health Dentistry, Sree Balaji Dental College and Hospital,

Pallikaranai, Chennai - 600100, India.

2Assistant Professor in Periodontics, College of Dentistry, Department of Periodontics,

Ajman University, Ajman, UAE.

3Department of Prosthodontics, Sree Balaji Dental College and Hospital,

BIHER, Pallikaranai,  Chennai-600100, India.

*Corresponding Author E-mail: drvidhyarekha@gmail.com

 

ABSTRACT:

Cancer is a one of the leading causes of death in the world, continue to be worldwide eradicator. Multi-drug resistance (MDR) is a major problem with the current treatment options. It is now widely believed that many herbal dietary products are available as chemoprotective agents against commonly occurring cancer types. Piperine is an alkaloid; exhibit a wide spectrum of biological and pharmacological activities like anti-pyretic, antimetastatic, antidepressant, antiapoptotic and antitumor activity. In this review, to focus effect of piperine on anticancer research related to their mechanism of action and its ability to regulate cancer related gene action like oncogenic and tumour supprosser gene in cycle and apoptosis as well as its therapeutic perspectives on oral cancer, online-literature were studied which includes books on phytochemistry and the electronic search (SciFinder, Pubmed, the Web of Science, Scopus, Google Scholar and etc). Piperine action on apoptosis pathway via caspases signalling has been studied in many researches, in which piperine disrupts cell proliferation and induces apoptosis. Piperine had the ability to cause cell cycle arrest in G2/M phase and to activate caspase-3 and caspase-9 cascades showed selective cytotoxicity and also through the downregulation of cyclin B1 and enhanced phosphorylation of cyclin-dependent kinase-1 (CDK1) and check point kinase 2 in cell cycle. It also inhibits the functions of P-glycoprotein (P-gp) and CYP3A4, which not only affects drug metabolism but also re-sensitizes multidrug resistant (MDR) cancer cells. Anti-proliferative and pro-apoptotic nature of Piperine extends its activity by stabilizing the G-quadruplex structure formed at c-myc promoter region and down regulating its expression in cancer cells. Since there is very less evidence on oral cancer piperine strength the prospective to treat oral cancer as its usefulness for the above said molecular mechanism associate with other cancer. This shows the postern to piperine against oral cancer research. Further impost of the anticancer potency of piperine on in vivo and clinical trials need to be studied for anticancer drug development in oral cancer treatment.

 

KEYWORDS: Oral Cancer, Piperine, Apoptosis, Cell cycle arrest, Caspases, Therapeutic perspectives.

 

 


1. INTRODUCTION:

Cancer is emerging as a major problem globally, characterized by the uncontrolled growth and spread of abnormal cells as leading cause of morbidity and mortality worldwide.

 

Statistics indicate that 18.1 million new cancer cases and 9.6 million cancer deaths occurred globally in 20181. The etiological factors include cigarette smoking, environmental carcinogens, ultraviolet (UV) exposure, inheritance, stress, obesity, and physical inactivity in which unhealthy diet plays the huge role in development of cancer. As in all cancer related deaths, 30–35% is linked to diet, almost 25–30% is due to tobacco, about 15–20% is due to infections and only 5–10% is due to genetic defects (mutations) which are inherited from a parent2. Therefore, Cancer continues to be worldwide eradicator, it is essential to search for naturally occurring drugs to minimize health problems. The studies indicate that many herbal dietary products are available as chemoprotective agents against commonly occurring cancer types3. The development of novel anticancer agents is contingent on alternation in cell cycle, regulation of apoptotic cascades at molecular level along with oncogene regulations4.

 

Piperine, an alkaloid and hydrophobic amide, is a major constituent of Piper nigrum (Black pepper) and Piper longum of Piperaceaefamily5. Traditionally, pepper has been used for many ailments such as stomach upset, bronchitis, malaria, cholera and cancer6. Piperine exhibited a wide spectrum of biological and pharmacological activities7,8 like anti-pyretic9, antimetastatic10, antidepressant11, antiapoptotic efficacy12, high immunomodulatory and antitumor activity13. In this review, we mainly focus on the Piperine anticancer research related to their mechanism of action and the guidelines in place for their regulations.

 

2. Pathogenesis and pathophysiology of cancer:

Carcinogenesis is a multi-step process in which cells undergo metabolic and behavioural changes, leading them to proliferate in an excessive and untimely way to invade distant tissues to form metastases. These changes arise through the accumulation of modifications in the genetic programmes that control cell proliferation and lifespan, relationships with neighbouring cells, and capacity to escape the immune system14. Hence, detecting mutations in cancer cells has many potential implications for research and therapy15. The most studied cancer genes is TP53, which encodes the p53 protein, a tumour suppressor that is mutated in about half of all human cancer cases, compiles about 24 000 TP53 mutations. But to become cancerous, this cell must acquire several changes in oncogenes and tumour suppressor genes that will make the cell capable of proliferating well beyond its normal limit. Human cells become malignant through the activation of oncogenes include growth factors (e.g. TGFA), growth factor receptors (e.g. the receptors for epidermal growth factor, EGF and its close homologue,ERBB2), receptor-coupled signal transduction molecules (in particular, several small guanosine triphosphate (GTP)- binding proteins located on the inner face of the cell membrane, such as the various members of the RAS family), kinases(SRC, ABL, RAF1), regulatory subunits of cell cycle kinases (CCND1 and CCNA), phosphatases (CDC25B), anti-apoptotic molecules (BCL2) and transcription factors (MYC, MYB, FOS, JUN) along with the inactivation of tumour suppressor genes like in which two of them, p53 and CDKN2A, are very commonly altered in almost every kind of human cancer16,17. Apoptosis, or lack of it, may be critical to tumorigenesis along with the above believed regulation of oncogene and tumour suppressor gene using a variety of relevant signalling pathways18. Apoptosis and its regulatory genes are the key mechanisms of anticancer drugs in cancer therapy and have emerged as an effective target for the discovery and development of novel anticancer agents as there are plant-derived products and relatively nontoxic in nature19.

 

3. Piperine in Cancer Research:

Recent research proven that piperine has been very good antimetastatic properties against breast cancer20, lung cancer21, human fibrosarcoma22, human rectal tumor23, prostate cancer24. It major act by inhibiting the oncogenesis of above said tumors and its related protein via transcriptional level includes NF-κB, c-Fos, cAMP response element-binding (CREB), matrix metalloproteinase (MMP) -9 expression, the functions of P- glycoprotein (P-gp),CYP3A425 and HER2 gene expression. Piperine also extends its action by caspase-3 and caspase-9 cascades in Apoptosis26. Piperine can inhibit tumor growth by inducing cell apoptosis, depolarization of mitochondrial membrane potential, cell cycle blockage, caspase-3,7 and caspase-9 activation could be an attractive and promising alkaloid to develop anticancer drugs and oral cancer therapy.

 

3.1 Piperine in apoptosis pathway via caspases signalling:

Apoptosis is primarily initiated through two main signaling pathways: the death receptor (extrinsic) and mitochondria mediated (intrinsic) pathways27. Apoptotic cell death by dysregulation of caspases (cysteinyl aspartate-specific proteases family) may cause various diseases in humans such as cancer and inflammatory disorders28. Caspase sigalling was categorized as the initiator caspases (caspases-8, -9, and 10) and the effector caspases (caspases-3, -6, and -7) in which activation of caspases-3 and -7 is essential for inducing downstream DNA cleavage molecules, which is involved with both extrinsic and intrinsic apoptotic pathways29. Piperine action on apoptosis pathway via caspases signalling has been studied in many researches. Piperine effectively inhibited the proliferation of prostate cancer cells and induced apoptosis via cleavage of PARP-1, inhibition of phosphorylated STAT-3 (transcription proteins), inhibition of NF-kB expression may represent the molecular mechanism by which piperine disrupts cell proliferation and induces apoptosis in prostate cancer cells30.

 

Piperine have been found to induce apoptosis by primarily targeting the activation of caspases 3 and 9 in prostate cancer cell was also been studied by Gnanasekar et al.31 Piperine had the ability to cause cell cycle arrest in G2/M phase and to activate caspase-3 and caspase-9 cascades showed selective cytotoxicity toward lung cancer cell line (A549)26. Piperine demonstrated significant potential against STAT3/NF-kB in human cervical cancer; ovarian cancer and hela cervix cell line inhibited cell viability and caused apoptosis via JNK/p38 MAPK-mediated intrinsic apoptotic pathway32,33. Do et al.34 study on HER2 overexpressing breast cancer cells demonstrated inhibited proliferation and induced apoptosis by activating caspase-3 and cleavage of PARP on piperine treatment. These studies revealed that piperine inhibit tumor growth by inducing cell apoptosis via caspase signalling activation.

 

3.2 Piperine action in oncogene and tumour suppressor gene:

Oncogenes are cellular or viral (i.e., inserted into the cell by a virus) genes; their expression can cause the development of a neoplasm. Protooncogenes are normal cellular genes; their conversion to oncogenes can occur via several mechanisms such as amplification or modification35-37 and can transform normal cells into cancer cells when over-expressed or tumor suppressor genes in opposite ways38,39. In cancer cells, transcription factors that regulate proliferation, inflammatory, angiogenesis, invasive and apoptosis resistance by induction of several proteins, such as cyclin D, cyclin E1, CDK2, CDK4, CDK6, c-myc, tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, IL-8, VEGF and MMP-940 hall mark at trancsriptional level changes in tumor cells. Piperine is a potent inhibitor of NF-κB, c-Fos, cAMP response element-binding (CREB), activated transcription factor 2 (ATF-2), among others41. It suppresses PMA-induced MMP-9 expression via the inhibition of PKCα/extracellular signal-regulated kinase (ERK) ½ and reduction of NF-κB/AP-1 activation42. Remarkably, piperine also inhibits the functions of P-glycoprotein (P-gp) and CYP3A4, which not only affects drug metabolism but also re-sensitizes multidrug resistant (MDR) cancer cells43,44. Oral supplementation of piperine markedly reduced the DNA damage and DNA-protein crosslinks in experimental model of benzo (a) pyrene induced lung cancer45. Piperine appears to extend its chemopreventive specificity for G-quadruplex DNA over double stranded DNA, with highest affinity for G-quadruplex structure formed at c-myc promoter region. G- quadruplex DNA structures are four stranded DNA structures that are generated by square planar arrangement of G-quartets during DNA metabolism and play vital role in regulation of cellular processes that might contribute to cancer development. Piperine shows concentration dependent cytotoxicity in HeLa, PC3, HepG2 and MCF-7 cell lines along with the down-regulation of c-myc gene relative to a constitutively expressed housekeeping gene, β -actin. Piperine has highest affinity for c-myc promoter region DNA sequence (Pu24T) forming G-quadruplex structure. An idea of anti-proliferative and pro-apoptotic nature of Piperine and it exerts its anti-cancer activity could be by stabilizing the G-quadruplex structure formed at c-myc promoter region and down regulating its expression in cancer cells46.

 

3.3 Piperine in cell cycle arrest:

Progression through the cell cycle is primarily controlled by cyclins, associated kinases and their inhibitors. Cancer may be perceived as the consequence of loss of cell cycle control and Progressive genetic instability47. Members of the cyclin family of proteins are key regulators of the cell cycle. Cyclins bind and activate members of the cyclin-dependent kinase (Cdk) family to control cell cycle progression. During the G1 phase, cyclins D1, D2, and D3 form complexes with cdk4 or cdk6, and cyclin E with cdk2, to modulate the expression of proliferative genes. Cyclin A associates with cdk2 during the S phase, and with cdc2 (cdk1) at the S-G2 boundary and into G2. Progression through G2, culminating in mitosis, further requires that cdc2 form complexes with cyclins B1 and B2. Piperine treatment down-regulated the expression of cyclin B1 in 4T1 cells with a dose-dependent manner48. Piperine arrests osteosarcoma cells at G2/M phase of cell cycle through the downregulation of cyclin B1 and enhanced phosphorylation of cyclin-dependent kinase-1 (CDK1) and checkpoint kinase 2 (Chk2)49. Piperine can inhibit tumor growth by inducing cell cycle blockage.

 

3.4 Piperine as potent anticancer agent:

The scientific evidence provided supports mechanisms of piperine action, which are related to its anti- inflammatory, immunomodulatory, anti-mutagenic and anti-cancer activities, together with its ability to interfere with several molecular signaling pathways. Anti-proliferative and pro-apoptotic nature of Piperine promising as cancer chemopreventive agent by regulating the apoptotic pathway and by cell cycle arrest. Its antitumor potential demonstrated through its apoptotic mode on many cancer types, should be further investigated, especially in the form of human clinical trials, since such data do not exist.

 

4. Therapeutic role of piperine on oral cancer:

Worldwide, oral cancer accounts for 2%–4% of all cancer cases. Oral cancer includes a group of neoplasms affecting any region of the oral cavity, pharyngeal regions and salivary glands. However, this term oral squamous cell carcinoma (OSCC) represents the most frequent of all oral neoplasms50. The more common premalignant lesions including leukoplakia, erythroplakia, oral lichen planus and oral submucous fibrosis have varying potential for malignant transformation51. Currently, targeted molecular therapy, like therapy with monoclonal antibodies and gene therapy, has been applied to oral cancer patients. This treatment modality has limited or non-existent side effects on normal cells of the body, unlike surgery, chemotherapy, and radiotherapy. Targeted molecular therapy can also act as a complement to other existing cancer therapies and has been mainly focused on four molecules; epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor (PPAR), and progesterone receptor. These molecules are associated with the proliferation and the differentiation of OSCC52. There is limited evidence for an oral cancer-prevention or the treatment, piperine strength the prospective to treat oral cancer as its usefulness for the above said molecular mechanism associate with other cancer. This shows the postern to piperine against oral cancer research. Hence not much evidence on such research, Siddiqui et al.53 reported piperine stimulates the generation of ROS in human oral squamous cells which in turn leads to dissipation of mitochondrial membrane potential (MMP), activation of caspases, and cell cycle arrest. Piperine stimulated cell death by inducing loss of MMP, and caspase-3 activation. Cell cycle study revealed that piperine arrested the cells in G2/M phase and decreased the DNA content. This study suggests the efficacy of piperine in oral cancer research.

 

5. CONCLUSION:

Literature survey on animal models have shown that piperine has potential anti-proliferative and pro- apoptotic nature and it extends its activity by stabilizing the G-quadruplex structure formed at c-myc promoter region and down regulating its expression. There is very less evidence on oral cancer that piperine strength the prospective to treat oral cancer as its usefulness for the above said molecular mechanism associate with other cancer. This shows the postern to piperine against oral cancer research. Further impost of the anticancer potency of piperine on in vivo and clinical trials need to be studied for anticancer drug development in oral cancer treatment for future.

 

6. REFERENCE:

1.      J. Ferlay, M. Colombet, I. Soerjomataram, C. Mathers, D.M. Parkin, M. Pineros, A. Znaor, F. Bray, Estimating the global cancer incidence and mortality in 2018: Globocan Sources and Methods, Int. J. Cancer 144 (2019) 1941–1953.

2.      Preetha Anand, Ajaikumar B. Kunnumakara, Chitra Sundaram, Kuzhuvelil B. Harikumar, Sheeja T. Tharakan, Oiki S. Lai, Bokyung Sung, Bharat B. Aggarwal, Cancer is a Preventable Disease that Requires Major Lifestyle Changes, Pharmaceutical Research, Vol. 25, No. 9, September 2008

3.      S.B. Prabha, Mohini Rao, M. R. Ramesh Kumar. Evaluation of in vitro Antioxidant, Antibacterial and Anticancer activities of leaf extracts of Cleome rutidosperma. Research J. Pharm. and Tech. 2017; 10(8): 2492-2496. doi: 10.5958/0974-360X.2017.00440.1

4.      Chandrasekar. R, Sivagami. B, M. Niranjan Babu. A Pharmacoeconomic Focus on Medicinal Plants with Anticancer Activity. Res. J. Pharmacognosy and Phytochem. 2018; 10(1): 91-100. doi: 10.5958/0975-4385.2018.00015.8

5.      Szallasi. Piperine: researchers discover new flavor in an ancient spice,. Trends in Pharmacological Sciences, vol. 26, no. 9, pp. 437–439, 2005.

6.      Yenduri Suvarna, S K. Abdul Rahaman. In Vitro – In Vivo Evaluation of Antiurolithiatic activity of piperine from Piper nigrum. Research J. Pharm. and Tech. 2020; 13(1):63-68. doi: 10.5958/0974-360X.2020.00011.6

7.      K. Srinivasan, “Black pepper and its pungent principlepiperine:a review of diverse physiological effects,” Critical Reviews in Food Science and Nutrition, vol. 47, no. 8, pp. 735–748, 2007.

8.      Bezerra DP, Castro FO, Alves APNN, Pessoa C, Moraes MO, Silveira ER, Lima MAS, Elmiro FJM, Costa-Lotufo LV (2006) In vivo growth-inhibition of Sarcoma 180 by piplartine and piperine, two alkaloid amides from Piper. J Med Biol Res 39:801–807

9.      Parmar VS, Jain SC, Bisht KS, Jain R, Taneja P, Jha A, Tyagi OD, Prasad AK, Wengel J, Olsen CE, Boll PM (1997) Phytochemistry of the genus Piper. Phytochemistry 46:597–673.

10.   Rutuja Sawant, Aloka Baghkar, Sanjukta Jagtap, Lina Harad, Anagha Chavan, Nilofar A. Khan, Rupali P. Yevale, Mohan K. Kale. A Review on - Herbs in Anticancer. Asian J. Res. Pharm. Sci. 2018; 8(4):179-184. doi: 10.5958/2231-5659.2018.00031.0

11.   Mohammed Shakir Ghouse. An Overview on plant derived Anticancer Drugs. Res. J. Pharmacognosy and Phytochem. 2020; 12(4):235-244. doi: 10.5958/0975-4385.2020.00040.0

12.   Mayur S. Jain, Mayur R. Bhurat, Sunil R Bavaskar. Melphalan flufenamide is an Anticancer medication used to treat multiple Myeloma: A Review. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(4):291-4. doi: 10.52711/2231-5659.2021.00045

13.   Anita S. Kulkarni, Remeth J. Dias, Vishwajeet S. Ghorpade, Kailas K Mali. Freeze dried Multicomponent Inclusion Complexes of Piperine with Cyclodextrin and Hydrophilic Polymers: Physicochemical Characterization and In vivo Anti-inflammatory Activity. Research J. Pharm. and Tech. 2020; 13(10):4916-4924. doi: 10.5958/0974-360X.2020.00864.1

14.   Arti Mohan, G. Sangeetha. Formulation and Evaluation of Immediate Release Film Coated Tablets of An Anticancer Drug (Dasatinib). Research J. Pharm. and Tech 2019; 12(2):729-734. doi: 10.5958/0974-360X.2019.00129.X

15.   Loeb LA, Bielas JH, Beckman RA (2008). Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68: 3551-3557.

16.   Rupa Bhattacharya, Prajakta Naitam. Green Anticancer Drugs – An Review. Res. J. Pharmacognosy and Phytochem. 2019; 11(4): 231-243. doi: 10.5958/0975-4385.2019.00040.2

17.   Hunter T (1991) Cooperation between oncogenes. Cell, 64: 249-270.

18.   Choisy-Rossi C, Yonish-Rouach E (1998) Apoptosis and the cell cycle: the p53 connection. Cell Death Differ, 5: 129-131.

19.   Nandhini S, Radha R , Vadivu R. Docking of Hematoporphyrin on Various Anticancer Drugs Targeting Enzymes. Asian J. Pharm. Res. 2016; 6(3): 123-130. doi: 10.5958/2231-5691.2016.00019.8

20.   Do MT, Kim HG, Choi JH, Khanal T, Park BH, Tran TP, et al. Antitumor efficacy of piperine in the treatment of human HER2‑overexpressing breast cancer cells. Food Chem 2013;141:2591‑9.

21.   Hwang YP, Yun HJ, Kim HG, Han EH, Choi JH, Chung YC, et al. Suppression of phorbol‑12‑myristate‑13‑acetate‑induced tumor cell invasion by piperine via the inhibition of PKC alpha/ERK1/2‑dependent matrix metalloproteinase‑9 expression. Toxicol Lett 2011;203:9‑19.

22.   Y. P. Hwang, H. J. Yun, H. G. Kim et al., “Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCα/ERK1/2-dependent matrix metalloproteinase-9 expression,” Toxicology Letters, vol. 203, no. 1, pp. 9–19, 2011.

23.   Yaffe PB, Doucette CD, Walsh M, Hoskin DW. Piperine impairs cell cycle progression and causes reactive oxygen species‑dependent apoptosis in rectal cancer cells. Exp Mol Pathol 2013;94:109‑14.

24.   Ouyang DY, Zeng LH, Pan H, Xu LH, Wang Y, Liu KP, et al. Piperine inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and autophagy. Food ChemToxicol 2013;60:424‑30.

25.   C. R. Pradeep and G. Kuttan, “Piperine is a potent inhibitor of nuclear factor-κB (NF-κB), c-Fos, CREB, ATF- 2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells,” International Immunopharmacology, vol. 4, no. 14, pp. 1795–1803, 2004.

26.   Lin Y, Xu J, Liao H, Li L, and Pan L: Piperine induces apoptosis of lung cancer A549 cells via p53- dependent mitochondrial signaling pathway. TumorBiol 35, 3305–3310, 2014.

27.   Czabotar, P. E., Lessene, G., Strasser, A., and Adams, J. M. (2014). Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49–63.

28.   Looi, C. Y., Arya, A., Cheah, F. K., Muharram, B., Leong K, H., Mohamad, K., et al. (2013). Induction of apoptosis in human breast cancer cells via caspase pathway by vernodalin isolated from Centratherumanthelminticum (L). seeds. PLoS One 8, e56643.

29.   Wu, H., Che, X., Zheng, Q., Wu, A., Pan, K., Shao, A., et al. (2014). Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. Int. J. Biol. Sci. 10, 1072–1083.

30.   Abhilash Samykutty, Aditya Vittal Shetty, Gajalakshmi Dakshinamoorthy, Mary Margaret Bartik, Gary Leon Johnson, Brian Webb, Guoxing Zheng, Aoshuang Chen, Ramaswamy

31.   Gnanasekar M, Thirugnanam S, Zheng G, Chen A, Ramaswamy K (2009) Gene silencing of translationally controlled tumor protein (TCTP) by siRNA inhibits cell growth and induces apoptosis of human prostate cancer cells. Int J Oncol 34:1241–6.

32.   Han, S.-Z.; Liu, H.-X.; Yang, L.-Q.; Cui, L.; Xu, Y. Piperine (PP) enhanced mitomycin-C (MMC) therapy of human cervical cancer through suppressing Bcl-2 signaling pathway via inactivating STAT3/NF-B. Biomed. Pharmacother. 2017, 96, 1403–1410.

33.   Si, L.; Yang, R.; Lin, R.; Yang, S. Piperine functions as a tumor suppressor for human ovarian tumor growth via activation of JNK/p38 MAPK-mediated intrinsic apoptotic pathway. Biosci.Rep. 2018, 38, BSR20180503.

34.   Do, M.T.; Kim, H.G.; Choi, J.H.; Khanal, T.; Park, B.H.; Tran, T.P.; Jeong, T.C.; Jeong, H.G. Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells. Food Chem. 2013, 141, 2591–2599.

35.   Rabbits, T. H. (1994) Nature, 72, 143-149.

36.   Weinberg, R. A. (1995) Ann. N. Y. Acad. Sci., 758, 331-338.

37.   Zhou, Y., Ma, B. G., & Zhang, H. Y. (2007). Human oncogene tissue-specific expression level significantly correlates with sequence compositional features. FEBS Letters, 581, 4361–4365.

38.   Todd, R., and Wong, D. T. (1999). Oncogenes. Anticancer Research, 19(6A), 4729–4746.

39.   Mitsushita, J., David Lambeth, J., and Kamata, T. (2004). Thesuperoxide-generating oxidase Nox1 Is functionally required for Ras oncogene transformation. Cancer Research, 64, 3580–3585.

40.   Fan Y, Mao R, Yang J. NF‑κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013;4:176‑85.

41.   C. R. Pradeep and G. Kuttan, “Piperine is a potent inhibitor of nuclear factor-κB (NF-κB), c-Fos, CREB, ATF- 2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells,” International Immunopharmacology, vol. 4, no. 14, pp. 1795–1803, 2004.

42.   Y. P. Hwang, H. J. Yun, H. G. Kim et al., “Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCα/ERK1/2- dependent matrix metalloproteinase-9 expression,” Toxicology Letters, vol. 203, no. 1, pp. 9–19, 2011.

43.   R. K. Bhardwaj, H. Glaeser, L. Becquemont, U. Klotz, S. K. Gupta, and M. F. Fromm, “Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4,”Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 2, pp. 645–650, 2002.

44.   S. Li, Y. Lei, Y. Jia, N. Li, M. Wink, and Y. Ma, “Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes Pgp, MRP1 and BCRP dependent multidrug resistant cancer cells,” Phytomedicine, vol. 19, no. 1, pp. 83–87, 2011.

45.   Selvendiran, K., Prince Vijeya Singh, J., and 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.

46.   ArpitaTawani, Ayeman Amanullah, Amit Mishra and Amit Kumar, Evidences for Piperine inhibiting cancer by targeting human G-quadruplex DNA sequences, Scientific Reports, 6:39239, 2016

47.   Meeran, S. M., and Katiyar, S. K. (2008). Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front. Biosci. 13, 2191–2202.

48.   Li-hua LAI, Qi-hong FU, Yang LIU, Kai JIANG, Qing-ming GUO, Qing-yun CHEN, Bin YAN, Qing- qing WANG, Jian-gen SHEN, Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 murine breast cancer model, Acta Pharmacologica Sinica (2012) 33: 523–530

49.   Zhang, J., Zhu, X., Li, H., Li, B., Sun, L., Xie, T., et al. (2015). Piperine inhibits proliferation of human osteosarcoma cells viaG2/Mphase arrest and metastasis by suppressing MMP-2/-9 expression. Int. Immunopharmacol. 24, 50–58.

50.   Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 2008; 87: 14-32.

51.   Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. Journal of oral pathology andmedicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2007; 36(10):575–580.

52.   Hamakawa H, Nakashiro K, Sumida T, et al. Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer. Head Neck 2008; 30: 800-9.

53.   Siddiqui, S., Ahamad, M. S., Jafri, A., Afzal, M., and Arshad, M. (2017). Piperine triggers apoptosis of human oral squamous carcinoma through cell cycle arrest and mitochondrial oxidative stress. Nutr. Cancer 69, 791–799.

 

 

 

 

Received on 01.07.2020           Modified on 13.09.2021

Accepted on 21.03.2022         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(7):3338-3342.

DOI: 10.52711/0974-360X.2022.00558