Phenolic Compounds as Selective Antineoplasic Agents against Multidrug-resistant Human Cancer Cells

Abstract

Twelve phenolic compounds, including three stilbenes, two flavonoids, two coumarins, one neolignan, and four lignans, isolated from Euphorbia and Pycnanthus species or obtained by derivatization, were assayed for their potential antineoplastic efficacy in three human cancer cell lines: gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) carcinomas as well as derived multidrug-resistant sublines. In each case, two different multidrug-resistant variants, i.e., cell lines with classical and atypical MDR phenotype, were used. The majority of the MDR cancer sublines showed increased sensitivities to the studied compounds when compared to the parental sublines. The most active compound was the flavonoid naringenin, found to be 15-fold more effective against the atypical MDR subline of gastric carcinoma than in parental drug-sensitive cells. Furthermore, the stilbene trans-3,5,3′,4′-tetramethoxypiceatannol and the lignans 4′-hydroxy-3,3′,4-trimethoxylignan and heliobuphthalmin also exhibited high antineoplasic activities against the classical MDR subline derived from gastric carcinoma. The results of this study suggest that some phenolic compounds might be valuable for the treatment of multidrug-resistant cancer cells.

Key words

antiproliferatives - multidrug resistance - stilbenes - lignans - piceatannol - naringenin

References

• 1 O' Connor R, Clynes M, Dowling P, O' Donovan N, Driscoll L. Drug resistance in cancer – searching for mechanisms, markers and therapeutic agents.  Expert Opin Drug Metab Toxicol. 2007;  3 805-817
• 2 Lage H. An overview of cancer multidrug resistance: a still unsolved problem.  Cell Mol Life Sci. 2008;  65 3145-3167
• 3 Newman D, Cragg G. Natural products as sources of new drugs over the last 25 years.  J Nat Prod. 2007;  70 461-477
• 4 Jones W, Chin Y, Kinghorn D. The role of pharmacognosy in modern medicine and pharmacy.  Curr Drug Targets. 2006;  7 247-264
• 5 Saleem M, Kim H, Ali M, Lee Y. An update on bioactive plant lignans.  Nat Prod Rep. 2005;  22 696-716
• 6 Roupe K A, Remsberg C, Yánez J, Davies N. Pharmacometrics of stibenes: seguing towards the clinic.  Curr Clin Pharmacol. 2006;  1 81-101
• 7 Ferrigni N R, McLaughlin J L, Powell R G, Smith C R. Use of potato disc and brine shrimp bioassays to detect activity and isolate piceatannol as the antileukemic principle from the seeds of Euphorbia lagascae.  J Nat Prod. 1984;  4 347-352
• 8 Geahlen R L, McLaughlin J L. Piceatannol (3,4,3′,5′-tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor.  Biochem Biophys Res Commun. 1989;  165 241-245
• 9 Rimando A, Suh N. Biological/chemopreventive activity of stilbenes and their effect on colon cancer.  Planta Med. 2008;  74 1635-1643
• 10 Crozier A, Jaganath I, Clifford N. Dietary phenolics: chemistry, bioavailability and effects on health.  Nat Prod Rep. 2009;  26 1001-1043
• 11 Moon Y, Wang X, Morris M. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.  Toxicol In Vitro. 2006;  20 187-210
• 12 Ferreira M J U, Duarte N, Gyémánt N, Radics R, Chepernev G, Varga A, Molnár J. Interaction between doxorubicine and a resistance modifier stilbene in the antiproliferative effect on multidrug resistant mouse lymphoma and human breast cancer cells.  Anticancer Res. 2006;  26 3541-3546
• 13 Duarte N, Kayser O, Abreu P, Ferreira M J U. Antileishmanial activity of piceatannol isolated from Euphorbia lagascae seeds.  Phytother Res. 2008;  22 455-457
• 14 Duarte N, Ferreira M J U. Lagaspholones A and B: two new jatropholane-type diterpenes from Euphorbia lagascae.  Org Lett. 2007;  9 489-492
• 15 Duarte N, Lage H, Ferreira M J U. Three new jatrophane diterpene polyesters and other constituents from Euphorbia tuckeyana.  Planta Med. 2008;  74 61-68
• 16 Wesolowska O, Wiśniewski J, Duarte N, Ferreira M J U, Michalak K. Inhibition of MRP1 transport activity by phenolic and terpenic compounds isolated from Euphorbia species.  Anticancer Res. 2007;  27 4127-4134
• 17 Abrantes M, Mil-Homens T, Duarte N, Lopes D, Cravo P, Madureira M, Ferreira M J U. Antiplasmodial activity of lignans and extracts from Pycnanthus angolensis.  Planta Med. 2008;  74 1408-1412
• 18 Lage H, Aki-Sener E, Yalcin I. High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA Topoisomerase II-targeting drugs.  Int J Cancer. 2006;  119 213-220
• 19 Lage H, Duarte N, Coburger C, Hilgeroth A, Ferreira M J U. Antitumor activity of terpenoids against classical and atypical multidrug resistant cancer cells.  Phytomedicine. 2009;  DOI: 10.1016/j.phymed.2009.07.009
• 20 Lage H. Proteomic approaches for investigation of therapy resistance in cancer.  Proteomics Clin Appl. 2009;  3 883-911
• 21 Teisseyre A, Duarte N, Ferreira M J U, Michalak K. Influence of the multidrug transporter inhibitors on the activity of Kv1.3 voltage-gated potassium channels.  J Physiol Pharmacol. 2009;  60 69-76