. Sarmoko, Dyaningtyas Dewi Pamungkas P, Ratna Asmah Susidarti, Agung Endro Nugroho, Edy Meiyanto


Long-term use of doxorubicin causes cancer resistance due to overexpression of P-glycoprotein (P-gp), a protein that plays a role in cell drug efflux. The purpose of this study is to determine the action of hesperetin in increasing the cytotoxicity of doxorubicin on MCF-7 cancer cells resistant to doxorubicin (MCF-7/DOX) through suppression of P-gp expression. Cytotoxic assay of single and combinational treatment of doxorubicin and hesperetin were performed by using MTT assay. Apoptosis evidence was examined by using double staining with acridine orange and ethidium bromide dyes, while Pgp expression was determined by using immunocytochemistry. Hesperetin reduced cell viability in dose dependent manner. Both MCF-7 ori and MCF-7/DOX cells gave different responses to hesperetin with the IC50 values of >500μM and 267μM, respectively. Combining treatment of hesperetin and doxorubicin to MCF-7/DOX cells at the dose of 95μM and 230nM increased apoptosis evidence and suppressed P-gp expression. These results suggest that hesperetin enhances the anticancer effect of doxorubicin to resistance MCF-7 cells through suppression of P-gp expression.

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Bansal T., Jaggi M., Khar RK., Talegaonkar S. 2009. Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy. J Pharm Pharmaceut Sci, 12(1), 46-78.

Berman HM., Westbrook J., Feng Z., Gilliland G., Bhat TN., Weissig H., Shindyalov IN., Bourne PE. 2000. The Protein Data Bank. Nucleic Acids Res, 28(1), 235 – 42.

Borska S., Sopel M., Chmielewska M., Zabel M., Dziegiel P. 2010. Quercetin as A Potential Modulator of P-glycoprotein Expression and Function in Cells of Human Pancreatic Carcinoma Line Resistant to Daunorubicin. Molecules, 15(2), 857 – 70.

Chai S., To KKW., Lin G. 2010. Circumvention of Multi-drug Resistance of Cancer Cells by Chinese Herbal Medicines. Chin Med, 5:26.

Chung SY., Sung MK., Kim NH., Jang JO., Go EJ., Jeong LH. 2005. Inhibition of P-Glycoprotein by Natural Products in Human Breast Cancer Cells. Arch Pharm Res, 28(7), 823 – 828.

Emami A., Zeinali S., Motahari Z., Azizi E. 2005. Resistance to Adriamycin Alters the MDR1/P-gp, Topoisomerase II-alpha Gene and Protein Expression Levels in T47D Human Breast Cancer Cells, Conference Module of 2005 AAPS Annual Meeting and Exposition, downloaded from: www.aapsj.orgabstract AM_2005AAPS2005-001197.pdf, on 2 April 2012.

Gilmore TD., 2006, Introduction to NF-κB: Players, Pathways, Perspectives. Oncogene, 25, 6680 – 6684.

Hadjeri M., Barbier M., Ronot X., Mariotte AM., Boumendjel A., Boutonnat J. 2003. Modulation of P-Glycoprotein-Mediated Multidrug Resistance by Flavonoid Derivatives and Analogues. J Med Chem, 46, 2125-31.

Hermawan A., Meiyanto E., Susidarti RA. 2010. Hesperidin Meningkatkan Aktivitas Sitotoksik Doxorubicin pada Sel MCF-7. Majalah Farmasi Indonesia, 21(1), 8 – 17.

Ikegawa T., Ohtani H., Koyabu N., Juichi M., Iwase Y., Ito C., Furukawa H., Naito M., Tsuruo T., Sawada Y. 2002. Inhibition of P-glycoprotein by Flavonoid Derivatives in Adriamycin Resistant Human Myelogenous Leukemia (K562/ADM) Cell. Cancer Lett, 177, 89 – 93.

Khantamat O., Chaiwangyen W., Limtrakul P. 2004. Screening of Flavonoids for Their Potential Inhibitory Effect on P-glycoprotein Activity in Human Servical Carcinoma KB Cell. Chiang Mai Med Bull, 43(2), 45 – 56.

Kumar UN., Sailendra M., Peddanna K., Prasad ME., Deepika G., Seshapani P., Latha SL., Jayasimha DR. (2011).Virtual Screening of Flavonoid as Inhibitory Agents of P-Glycoprotein. IJABPT, 2(3), 130 – 140.

Lentini A., Forni C., Provenzano B., Beninati S. 2007. Enhancement of Transglutaminase Activity and Polyamine Depletion in B16-F10 Melanoma Cells by Flavonoids Naringenin and Hesperitin Correlate to Reduction of the In vivo Metastatic Potential. Amino Acids 2, 32(1), 95 – 100.

Li X., Lu Y., Liang K., Liu B., Fan Z. 2005. Differential Responses to Doxorubicin-Induced Phosphorylation and Activation of Akt in Human Breast Cancer Cells. Breast Cancer Res, 7(5), R589-R597.

Meiyanto E., Hermawan A., Anindyajati, 2012. Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents. Asian Pac. J. Cancer Prev., 13(2), 427-436.

Putri DDP., Sarmoko, Febriansah R., Puspitasari E., Ismiyati N., Fitriasari A. 2012. MCF-7 Resistant Doxorubicin are Characterized by Lamellipodia, Strong Adhesion on Substrate and Pgp Overexpression. Indo J Can Chemoprev, 2(3), 304-308.

Ugocsai K., Varga A., Molnar P., Antus S., Molnar J. 2005. Effects of Selected Flavonoids and Carotenoids on Drug Accumulation and Apoptosis Induction in Multidrug-resistant Colon Cancer Cells Expressing MDR1/LRP. In Vivo, 19, 433 – 438.

Ullah MF. 2008. Cancer Multidrug Resistance (MDR): A Major Impediment to Effective Chemotherapy. Asian Pacific J Cancer Prev, 9, 1 – 6.

Wang S., Kotamraju S., Konorev E., Kalivendi S., Joseph J., Kalyanamaran B., 2002, Activation of Nuclear Factor-kB during Doxorubicin-induced Apoptosis in Endothelial Cells and Myocytes is Pro-apoptotic: the Role of Hydrogen Peroxide, Biochem. J., 367: 729 – 740.

Wong HL., Bendayan R., Rauth AM., Xue HY., Babakhanian K., Wu XY. 2006. A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System. J Pharmacol Exp Ther, 317(3), 1372 – 1381.



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