PIPERINE IN THE PREVENTION OF THE DECREASED TAMOXIFEN SENSITIVITY IN MCF-7 BREAST CANCER CELL LINE
Keywords:P-glycoprotein, Piperine, Tamoxifen
Objective: This study was designed to analyze the role of piperine in modulating P-glycoprotein mRNA expression when added in combination with
tamoxifen to breast cancer cells in culture.
Methods: MCF-7 breast cancer cells were treated with 1 Î¼M tamoxifen with or without piperine (12.5, 25, or 50 Î¼M) or verapamil 50 Î¼M (P-glycoprotein
inhibitor positive control) for up to 12 days. We assessed the cell viability and isolated total RNA from them. We quantified P-glycoprotein expressions
using quantitative reverse transcription polymerase chain reaction.
Results: Administration of various doses of piperine decreased MCF-7 breast cancer cell viability. Piperine, when given in combination with tamoxifen,
decreased the expression of P-glycoprotein mRNA in cells compared with the expression in cells treated with tamoxifen only. The effects were shown
to be dose dependent.
Conclusion: Piperine prevents the development of breast cancer cell tamoxifen resistance, probably through its inhibition of P-glycoprotein expression.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C,
Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional,
and national cancer incidence, mortality, years of life lost, years lived
with disability, and disability-adjusted life-years for 32 cancer groups,
to 2015: A systematic analysis for the global burden of disease
study. JAMA Oncol 2017;3:524-48.
Apuri S. Neoadjuvant and adjuvant therapies for breast cancer. South
Med J 2017;110:638-42.
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A,
et al. Anastrozole is superior to tamoxifen as first-line therapy for
advanced breast cancer in postmenopausal women: Results of a North
American multicenter randomized trial. Arimidex study group. J Clin
Mouridsen H, Gershanovich M, Sun Y, PÃ©rez-CarriÃ³n R, Boni C,
Monnier A, et al. Superior efficacy of letrozole versus tamoxifen as
first-line therapy for postmenopausal women with advanced breast
cancer: Results of a Phase III study of the international letrozole breast
cancer group. J Clin Oncol 2001;19:2596-606.
Eckford PD, Sharom FJ. ABC efflux pump-based resistance to
chemotherapy drugs. Chem Rev 2009;109:2989-3011.
Harmsen S, Meijerman I, Febus CL, Maas-Bakker RF, Beijnen JH,
Schellens JH, et al. PXR-mediated induction of P-glycoprotein by
anticancer drugs in a human colon adenocarcinoma-derived cell line.
Cancer Chemother Pharmacol 2010;66:765-71.
Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug
Target Insights 2013;7:27-34.
Bansal T, Jaggi M, Khar RK, Talegaonkar S. Emerging significance
of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy.
J Pharm Pharm Sci 2009;12:46-78.
Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM.
P-glycoprotein inhibitors of natural origin as potential tumor chemosensitizers:
A review. J Adv Res 2015;6:45-62.
Aher S, Biradar S, Gopu CL, Paradkar A. Novel pepper extract
for enhanced P-glycoprotein inhibition. J Pharm Pharmacol
Singh A, Duggal S. Piperine-review of advances in pharmacology. Int J
Pharm Sci Nanotech 2009;2:615-20.
Louisa M, Sugiarti L, Kurniawan SV, Wanandi SI. Curcumin increases
anti-cancer activity of tamoxifen in MCF-7 breast cancer cells
through the suppression of MDR1 mRNA expression. Adv Sci Lett
Livak KJ, Schmittgen TD. Analysis of relative gene expression data
using real-time quantitative PCR and the 2(-delta delta C(T)) method.
Yang K, Wu J, Li X. Recent advances in the research of P-glycoprotein
inhibitors. Biosci Trends 2008;2:137-46.
Lykkesfeldt AE, Madsen MW, Briand P. Altered expression of
estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and
ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1.
Cancer Res 1994;54:1587-95.
Lin JH. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev 2003;55:53-81.
Purushothaman A, Nandhakumar E, Sachdanandam P. Anticancer effect
of shemamruthaa (a phytochemical formulation) on 7, 12-dimethybenz
(a) anthracene induced mammary carcinoma in rats. Asian J Pharm Clin
Tapadiya G, Metku M, Deokate U, Khadabadi S, Saboo S, Sahu K.
Quantitatives estimation of piperine from pharmaceutical dosage form
by HPTLC. Asian J Pharm Clin Res 2009;2:47-50.
Patel S, Vyas N. Validated spectrofluorimetric method for estimation of
piperine in an ayurvedic formulation. Asian J Pharm Clin Res 2012;5:231-3.
Callaghan R, Higgins CF. Interaction of tamoxifen with the multidrug
resistance P-glycoprotein. Br J Cancer 1995;71:294-9.
Li S, Lei Y, Jia Y, Li N, Wink M, Ma Y, et al. Piperine, a piperidine
alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP
dependent multidrug resistant cancer cells. Phytomedicine
Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF,
et al. Piperine, a major constituent of black pepper, inhibits human
P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002;302:645-50.
Han Y, Chin Tan TM, Lim LY. In vitro and in vivo evaluation of the
effects of piperine on P-gp function and expression. Toxicol Appl
Beck WT, Grogan TM, Willman CL, Cordon-Cardo C, Parham DM,
Kuttesch JF, et al. Methods to detect P-glycoprotein-associated
multidrug resistance in patientsâ€™ tumors: Consensus recommendations.
Cancer Res 1996;56:3010-20.