Drug Resistance and Its Future Perspectives in Cancer Treatment

Main Article Content

Shawan Roy
Arup Kumar
Md. Shafikul Islam
Farhan Ahmed Rabbi
Partha Paul
Md. Mamun Mia
A K M Khairul Islam
Anik Kumar Ray

Abstract

Cancer is a disease of the cells, which are the body’s fundamental building blocks. Cancer falls out when abnormal cells grow in an uncontrolled way. These abnormal cells can damage or invade the surrounding tissues, or spread to other parts of the body, causing further damage or invasion of the surrounding tissues. Cancers can develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers is needed to take under extensive research for further development of treatment strategy. This review study outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how does inherent tumor cell heterogeneity play a role in drug resistance. It also describes the epigenetic modifications that can provoke drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review outlines with a discussion on the best treatment options for existing drug resistant cancers.

Keywords:
Cancer, drug resistance, DNA, RNA.

Article Details

How to Cite
Roy, S., Kumar, A., Islam, M. S., Rabbi, F. A., Paul, P., Mia, M. M., Islam, A. K. M. K., & Ray, A. K. (2020). Drug Resistance and Its Future Perspectives in Cancer Treatment. Asian Oncology Research Journal, 3(3), 26-46. Retrieved from https://journalaorj.com/index.php/AORJ/article/view/30114
Section
Review Article

References

Hayflick L. Human cells and aging. Scientific American. 1968;218(3):32-7.

Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: an overview. Cancers. 2014;6(3):1769-92.

Fidler IJ. The pathogenesis of cancer metastasis: The seed and soil'hypothesis revisited. Nature reviews cancer. 2003; 3(6):453-8.

Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancer therapeutics. Nature reviews Drug discovery. 2006;5(2):147-59.

Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica et Biophysica Acta (BBA)-Biomembranes. 1976;455(1):152-62.

Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986;47(3):381-9.

Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Molecular and cellular biology. 1989; 9(3):1346-50.

Watson JV. Introduction to flow cytometry. Cambridge University Press; 2004 Nov 11.

Longo-Sorbello GS. Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials. haematologica. 2001;86(2):121-7.

Guengerich FP. Cytochrome p450 and chemical toxicology. Chemical research in toxicology. 2008;21(1):70-83.

Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. The Lancet. 2013;381(9881):1943-55.

Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a brief review. Advanced pharmaceutical bulletin. 2017;7(3):339.

Krishna Vadlapatla R, Dutt Vadlapudi A, Pal D, K Mitra A. Mechanisms of drug resistance in cancer chemotherapy: coordinated role and regulation of efflux transporters and metabolizing enzymes. Current pharmaceutical design. 2013; 19(40):7126-40.

Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9(1):105-27.

Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences. 1998; 95(26):15665-70.

Fetsch PA, Abati A, Litman T, Morisaki K, Honjo Y, Mittal K, Bates SE. Localization of the ABCG2 mitoxantrone resistance-associated protein in normal tissues. Cancer letters. 2006;235(1):84-92.

Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP–dependent transporters. Nature Reviews Cancer. 2002;2(1):48-58.

Gillet JP, Efferth T, Remacle J. Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2007;1775(2):237-62.

Harmsen S, Meijerman I, Beijnen JH, Schellens JH. The role of nuclear receptors in pharmacokinetic drug–drug interactions in oncology. Cancer treatment reviews. 2007;33(4):369-80.

Wu CP, Hsieh CH, Wu YS. The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy. Molecular pharmaceutics. 2011;8(6):1996-2011.

Takara K, Sakaeda T, Okumura K. An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. Current pharmaceutical Design. 2006;12(3):273-86.

Zwelling LA, Hinds M, Chan D, Mayes J, Sie KL, Parker E, Silberman L, Radcliffe A, Beran M, Blick M. Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. Journal of Biological Chemistry. 1989;264(28): 16411-20.

Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry c/c of Biokhimiia. 2000; 65(1):95-106.

Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer. 2013;13(10):714-26.

Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989; 244(4905):707-12.

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over-expresses HER2. New England Journal of Medicine. 2001;344(11):783-92.

Bell DW, Gore I, Okimoto RA, Godin-Heymann N, Sordella R, Mulloy R, Sharma SV, Brannigan BW, Mohapatra G, Settleman J, Haber DA. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nature genetics. 2005;37(12):1315-6.

Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. New England Journal of Medicine. 2005; 352(8):786-92.

Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A. Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008;455(7215):971-4.

Mehta K, Fok JY. Targeting transglutaminase-2 to overcome chemoresistance in cancer cells. InDrug Resistance in Cancer Cells. Springer, New York, NY. 2009;95-114.

Zhang N, Yin Y, Xu SJ, Chen WS. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules. 2008; 13(8):1551-69.

Palmberg C, Koivisto P, Hyylinen E, Isola J, Visakorpi T, Kallioniemi OP, Tammela T. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. European urology. 1997;31:216-9.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer cell. 2007;12(4):395-402.

Dieras V, Vincent-Salomon A, Degeorges A, Beuzeboc P, Mignot L, De Cremoux P. Trastuzumab (Herceptin®) et cancer du sein: mécanismes de résistance. Bulletin du cancer. 2007;94(3):259-66.

Browne BC, Crown J, Venkatesan N, Duffy MJ, Clynes M, Slamon D, O'Donovan N. Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Annals of Oncology. 2011;22(1):68-73.

Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast cancer research and treatment. 2011;128(2):447-56.

Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80.

Al-Jamal HA, Jusoh SA, Yong AC, Asan JM, Hassan R, Johan MF. Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells. Asian Pac J Cancer Prev. 2014;15(11): 4555-61.

Hirayama C, Watanabe H, Nakashima R, Nanbu T, Hamada A, Kuniyasu A, Nakayama H, Kawaguchi T, Saito H. Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 cells. Pharmaceutical Research. 2008;25(4):827-35.

Nambu T, Araki N, Nakagawa A, Kuniyasu A, Kawaguchi T, Hamada A, Saito H. Contribution of BCR–ABL‐independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells. Cancer Science. 2010; 101(1):137-42.

Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, Gandhi V, Plunkett W. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood. 2006;107(6):2517-24.

Zahreddine H, Borden K. Mechanisms and insights into drug resistance in cancer. Frontiers in pharmacology. 2013;4:28.

Michael M, Doherty MM. Tumoral drug metabolism: Overview and its implications for cancer therapy. Journal of Clinical Oncology. 2005;23(1):205-29.

Shen H, He MM, Liu H, Wrighton SA, Wang L, Guo B, Li C. Comparative metabolic capabilities and inhibitory profiles of CYP2D6. 1, CYP2D6. 10, and CYP2D6. 17. Drug Metabolism and Disposition. 2007;35(8):1292-300.

McFadyen MC, Melvin WT, Murray GI. Cytochrome P450 enzymes: novel options for cancer therapeutics. Molecular Cancer Therapeutics. 2004;3(3):363-71.

Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P 450 pharmacogenetics and cancer. Oncogene. 2006;25(11):1679-91.

Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes & cancer. 2011;2(4):466-74.

Aas T, Børresen AL, Geisler S, Smith-Sørensen B, Johnsen H, Varhaug JE, Akslen LA, Lønning PE. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature medicine. 1996;2(7):811-4.

Soengas MS, Alarcon RM, Yoshida H, Hakem R, Mak TW, Lowe SW. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science. 1999; 284(5411):156-9.

Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47): 7369-75.

Manolitsas TP, Englefield P, Eccles DM, Campbell IG. No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer. British Journal of Cancer. 1997;75(9):1398.

Cumming RC, Lightfoot J, Beard K, Youssoufian H, O'Brien PJ, Buchwald M. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nature Medicine. 2001;7(7):814-20.

Gagnon JF, Bernard O, Villeneuve L, Têtu B, Guillemette C. Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clinical Cancer Research. 2006;12(6):1850-8.

Woolley PV, Tew KD, editors. Mechanisms of drug resistance in neoplastic cells: Bristol-myers cancer symposia. Elsevier; 2017.

Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. New England Journal of Medicine. 2006; 355(10):983-91.

Bonanno L, Favaretto A, Rosell R. Platinum drugs and DNA repair mechanisms in lung cancer. Anticancer Research. 2014;34(1):493-501.

Niero EL, Rocha-Sales B, Lauand C, Cortez BA, de Souza MM, Rezende-Teixeira P, Urabayashi MS, Martens AA, Neves JH, Machado-Santelli GM. The multiple facets of drug resistance: one history, different approaches. Journal of Experimental & Clinical Cancer Research. 2014;33(1):37.

Indran IR, Tufo G, Pervaiz S, Brenner C. Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2011;1807(6):735-45.

Backos DS, Franklin CC, Reigan P. The role of glutathione in brain tumor drug resistance. Biochemical pharmacology. 2012;83(8):1005-12.

Joncourt F, Buser K, Altermatt H, Bacchi M, Oberli A, Cerny T. Multiple drug resistance parameter expression in ovarian cancer. Gynecologic oncology. 1998; 70(2):176-82.

Green JA, Robertson LJ, Clark AH. Glutathione S-transferase expression in benign and malignant ovarian tumours. British journal of cancer. 1993;68(2):235-9.

Jardim BV, Moschetta MG, Leonel C, Gelaleti GB, Regiani VR, Ferreira LC, Lopes JR, de Campos Zuccari DA. Glutathione and glutathione peroxidase expression in breast cancer: An immunohistochemical and molecular study. Oncology reports. 2013;30(3):1119-28.

Yu P, Du Y, Cheng X, Yu Q, Huang L, Dong R. Expression of multidrug resistance-associated proteins and their relation to postoperative individualized chemotherapy in gastric cancer. World journal of surgical oncology. 2014; 12(1):307.

Ge J, Tian AX, Wang QS, Kong PZ, Yu Y, Li XQ, Cao XC, Feng YM. The GSTP1 105Val allele increases breast cancer risk and aggressiveness but enhances response to cyclophosphamide chemotherapy in North China. PloS one. 2013;8(6).

Kap EJ, Richter S, Rudolph A, Jansen L, Ulrich A, Hoffmeister M, Ulrich CM, Brenner H, Chang-Claude J. Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin. Pharmacogenetics and Genomics. 2014;24(7):340-7.

Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Advanced drug delivery reviews. 2013;65(13-14):1866-79.

Singh A, Settleman JE. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741-51.

Shang Y, Cai X, Fan D. Roles of epithelial-mesenchymal transition in cancer drug resistance. Current cancer drug targets. 2013;13(9):915-29.

Parkin B, Ouillette P, Li Y, Keller J, Lam C, Roulston D, Li C, Shedden K, Malek SN. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood, The Journal of the American Society of Hematology. 2013; 121(2):369-77.

Navin N, Krasnitz A, Rodgers L, Cook K, Meth J, Kendall J, Riggs M, Eberling Y, Troge J, Grubor V, Levy D. Inferring tumor progression from genomic heterogeneity. Genome research. 2010;20(1):68-80.

Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, McBride DJ. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109-13.

Baker EK, El-Osta A. The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer. Experimental cell research. 2003; 290(2):177-94.

Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer research. 2000;60(21):6039-44.

Arnold CN, Goel A, Boland CR. Role of hMLH1 promoter hypermethylation in drug resistance to 5‐fluorouracil in colorectal cancer cell lines. International journal of cancer. 2003;106(1):66-73.

Worm J, Kirkin AF, Dzhandzhugazyan KN, Guldberg P. Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells. Journal of Biological Chemistry. 2001;276(43):39990-40000.

Chang HG, Kim SJ, Chung KW, Noh DY, Kwon Y, Lee ES, Kang HS. Tamoxifen-resistant breast cancers show less frequent methylation of the estrogen receptor β but not the estrogen receptor α gene. Journal of molecular medicine. 2005; 83(2):132-9.

Christmann M, Pick M, Lage H, Schadendorf D, Kaina B. Acquired resistance of melanoma cells to the antineoplastic agent fotemustine is caused by reactivation of the DNA repair gene MGMT. International Journal of Cancer. 2001;92(1):123-9.

Izbicka E, MacDonald JR, Davidson K, Lawrence RA, Gomez L, Von DH. 5, 6 Dihydro-5'-azacytidine (DHAC) restores androgen responsiveness in androgen-insensitive prostate cancer cells. Anticancer Research. 1999;19(2A):1285-91.

Kern DH, Weisenthal LM. Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. JNCI: Journal of the National Cancer Institute. 1990;82(7):582-8.

McGuire WL, Kern DH, Von Hoff DD, Weisenthal LM. In vitro assays to predict drug sensitivity and drug resistance. Breast cancer research and treatment. 1988; 12(1):7-21.

Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer control. 2003; 10(2):159-65.

Akan I, Akan S, Akca H, Savas B, Ozben T. N‐acetylcysteine enhances multidrug resistance‐associated protein 1 mediated doxorubicin resistance. European journal of clinical investigation. 2004;34(10):683-9.

Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer cell international. 2005; 5(1):30.

Liscovitch M, Lavie Y. Cancer multidrug resistance: a review of recent drug discovery research. IDrugs. 2002;5(4):349-55.

Akan I, Akan S, Akca H, Savas B, Ozben T. Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: Effects of N-acetylcysteine and Buthionine sulfoximine. Cancer cell International. 2005;5(1):22.

Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annual review of pharmacology and toxicology. 1999;39(1): 361-98.

Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. The Oncologist. 2003;8(5):411-24.

Ferry DR, Traunecker H, Kerr DJ. Clinical trials of P-glycoprotein reversal in solid tumours. European Journal of Cancer. 1996;32(6):1070-81.

Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacological reviews. 1990;42(3):155-99.

Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. European Journal of Pharmaceutical Sciences. 2000;11(4):265-83.

Theis JG, Chan HS, Greenberg ML, Malkin D, Karaskov V, Moncica I, Koren G, Doyle J. Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma. Medical and Pediatric Oncology: The Official Journal of SIOP—International Society of Pediatric Oncology (Societé Internationale d'Oncologie Pédiatrique. 2000;34(4):242- 9.

Fischer V, Rodríguez-Gascón A, Heitz F, Tynes R, Hauck C, Cohen D, Vickers AE. The multidrug resistance modulator valspodar (PSC 833) is metabolized by human cytochrome P450 3A: implications for drug-drug interactions and pharmacological activity of the main metabolite. Drug Metabolism and Disposition. 1998;26(8):802-11.

van Zuylen L, Nooter K, Sparreboom A, Verweij J. Development of multidrug-resistance convertors: sense or nonsense?. Investigational new drugs. 2000;18(3):205-20.

Roe M, Folkes A, Ashworth P, Brumwell J, Chima L, Hunjan S, Pretswell I, Dangerfield W, Ryder H, Charlton P. Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. Bioorganic & Medicinal Chemistry Letters. 1999;9(4): 595-600.

Starling JJ, Shepard RL, Cao J, Law KL, Norman BH, Kroin JS, Ehlhardt WJ, Baughman TM, Winter MA, Bell MG, Shih C. Pharmacological characterization of LY335979: A potent cyclopropyldi-benzosuberane modulator of P-glycoprotein. Advances in Enzyme Regulation. 1997;37:335-47.

Newman MJ, Rodarte JC, Benbatoul KD, Romano SJ, Zhang C, Krane S, Moran EJ, Uyeda RT, Dixon R, Guns ES, Mayer LD. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Research. 2000;60(11):2964-72.

Necchi A, Vullo SL, Mariani L, Raggi D, Giannatempo P, Calareso G, Togliardi E, Crippa F, Di Genova N, Perrone F, Colecchia M. An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer. Investigational New Drugs. 2016;34(2):236-42.

Bouffard DY, Ohkawa T, Kijima H, Irie A, Suzuki T, Curcio LD, Holm PS, Sassani A, Scanlon KJ. Oligonucleotide modulation of multidrug resistance. European Journal of Cancer. 1996;32(6):1010-8.

Liu YY, Han TY, Giuliano AE, Hansen N, Cabot MC. Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance. Journal of Biological Chemistry. 2000;275(10):7138-43.

Lucci A, Giuliano AE, Han TY, Dinur TA, Liu YY, Senchenkov AL, Cabot MC. Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells. International Journal of Oncology. 1999;15(3):535-75.

Sarkadi B, Özvegy-Laczka C, Német K, Váradi A. ABCG2–a transporter for all seasons. FEBS letters. 2004;567(1):116-20.

Wilson WH. Chemotherapy sensitization by rituximab: experimental and clinical evidence. In Seminars in Oncology. 2000;27(6 Suppl 12):30-36.

Lozano C, Torres JL, Julià L, Jimenez A, Centelles JJ, Cascante M. Effect of new antioxidant cysteinyl‐flavanol conjugates on skin cancer cells. FEBS letters. 2005; 579(20):4219-25.

Kanadaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT, Lee MT. The antitumor activities of flavonoids. In vivo. 2005;19(5):895-909.

Sorrentino BP. Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs. Nature Reviews Cancer. 2002; 2(6):431-41.

Schoenfeld A, Luqmani Y, Sinnett HD, Shousha S, Coombes RC. Keratin 19 mRNA measurement to detect micrometastases in lymph nodes in breast cancer patients. British Journal of Cancer. 1996;74(10):1639-42.