Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Oncotarget

Volumn 8, Issue 24, 2017, Pages 38276-38293

  Zaccagnino, Angela ^a   Managò, Antonella ^b   Leanza, Luigi ^b   Gontarewitz, Artur ^a   Linder, Bernhard ^a   Azzolini, Michele ^b,c   Biasutto, Lucia ^b,c   Zoratti, Mario ^b,c   Peruzzo, Roberta ^b   Legler, Karen ^a   Trauzold, Anna ^a   Kalthoff, Holger ^a   Szabo, Ildiko ^b,c  

^a Kiel and Lungen Clinic Grosshansdorf   (Germany)

^b UNIVERSITY OF PADOVA   (Italy)

^c CNR   (Italy)

Author keywords

Apoptosis; Clofazimine; Orthotopic model; Pancreatic ductal adenocarcinoma; Potassium channel

Indexed keywords

CLOFAZIMINE; POTASSIUM CHANNEL KV1.3; PROTEIN P53; ANTINEOPLASTIC AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; CELL KILLING; CONTROLLED STUDY; DRUG ACCUMULATION; EC50; EMBRYO; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; MOUSE; NONHUMAN; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PROTEIN EXPRESSION; SINGLE DRUG DOSE; ANIMAL; DRUG EFFECT; DRUG SCREENING; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; SCID MOUSE; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; CLOFAZIMINE; HUMANS; KV1.3 POTASSIUM CHANNEL; MICE; MICE, SCID; PANCREATIC NEOPLASMS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 85020740232     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.11299     Document Type: Article

References (84)

1. Peixoto RD, Speers C, McGahan CE, Renouf DJ, Schaeffer DF and Kennecke HF. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer medicine. 2015; 4:1171-1177
2. Vincent A, Herman J, Schulick R, Hruban RH and Goggins M. Pancreatic cancer. Lancet (London, England). 2011; 378:607-620
3. Herreros-Villanueva M, Hijona E, Cosme A and Bujanda L. Adjuvant and neoadjuvant treatment in pancreatic cancer. World journal of gastroenterology. 2012; 18:1565-1572
4. Nagrial AM, Chin VT, Sjoquist KM, Pajic M, Horvath LG, Biankin AV and Yip D. Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. Critical reviews in oncology/hematology. 2015; 96:483-497
5. Philip PA and Lutz MP. Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer. Pancreas. 2015; 44:1046-1052
6. Safran H, Miner T, Bahary N, Whiting S, Lopez CD, Sun W, Charpentier K, Shipley J, Anderson E, McNulty B, Schumacher A, Clark A, Vakharia J, Kennedy T and Sio T. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. American journal of clinical oncology. 2011; 34:50-52
7. Ko AH, Youssoufian H, Gurtler J, Dicke K, Kayaleh O, Lenz HJ, Keaton M, Katz T, Ballal S and Rowinsky EK. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Investigational new drugs. 2012; 30:1597-1606
8. Leanza L, Manago A, Zoratti M, Gulbins E and Szabo I. Pharmacological targeting of ion channels for cancer therapy: in vivo evidences. Biochimica et biophysica acta.2015
9. Fraser SP, Ozerlat-Gunduz I, Brackenbury WJ, Fitzgerald EM, Campbell TM, Coombes RC and Djamgoz MB. Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2014; 369:20130105
10. Pardo LA and Stuhmer W. The roles of K(+) channels in cancer. Nature reviews Cancer. 2014; 14:39-48
11. Huang X and Jan LY. Targeting potassium channels in cancer. The Journal of cell biology. 2014; 206:151-162
12. Comes N, Serrano-Albarras A, Capera J, Serrano-Novillo C, Condom E, Ramon YCS, Ferreres JC and Felipe A. Involvement of potassium channels in the progression of cancer to a more malignant phenotype. Biochimica et biophysica acta. 2015; 1848:2477-2492
13. Comes N, Bielanska J, Vallejo-Gracia A, Serrano-Albarras A, Marruecos L, Gomez D, Soler C, Condom E, Ramon YCS, Hernandez-Losa J, Ferreres JC and Felipe A. The voltage-dependent K(+) channels Kv1.3 and Kv1.5 in human cancer. Frontiers in physiology. 2013; 4:283
14. Cahalan MD and Chandy KG. The functional network of ion channels in T lymphocytes. Immunological reviews. 2009; 231:59-87
15. Arcangeli A, Crociani O, Lastraioli E, Masi A, Pillozzi S and Becchetti A. Targeting ion channels in cancer: a novel frontier in antineoplastic therapy. Current medicinal chemistry. 2009; 16:66-93
16. Artym VV and Petty HR. Molecular proximity of Kv1.3 voltage-gated potassium channels and beta(1)-integrins on the plasma membrane of melanoma cells: effects of cell adherence and channel blockers. The Journal of general physiology. 2002; 120:29-37
17. Abdul M and Hoosein N. Reduced Kv1.3 potassium channel expression in human prostate cancer. J Membr Biol. 2006; 214:99-102
18. Abdul M, Santo A and Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer research. 2003; 23:3347-3351
19. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403:503-511
20. Leanza L, Trentin L, Becker KA, Frezzato F, Zoratti M, Semenzato G, Gulbins E and Szabo I. Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leukemia. 2013; 27:1782-1785
21. Szabo I, Trentin L, Trimarco V, Semenzato G and Leanza L. Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells. Cellular physiology and biochemistry. 2015; 37:965-978
22. Lan M, Shi Y, Han Z, Hao Z, Pan Y, Liu N, Guo C, Hong L, Wang J, Qiao T and Fan D. Expression of delayed rectifier potassium channels and their possible roles in proliferation of human gastric cancer cells. Cancer biology & therapy. 2005; 4:1342-1347
23. Brevet M, Fucks D, Chatelain D, Regimbeau JM, Delcenserie R, Sevestre H and Ouadid-Ahidouch H. Deregulation of 2 potassium channels in pancreas adenocarcinomas: implication of KV1.3 gene promoter methylation. Pancreas. 2009; 38:649-654
24. Jang SH, Choi SY, Ryu PD and Lee SY. Antiproliferative effect of Kv1.3 blockers in A549 human lung adenocarcinoma in vitro and in vivo. European journal of pharmacology. 2011; 651:26-32
25. Szabo I, Bock J, Jekle A, Soddemann M, Adams C, Lang F, Zoratti M and Gulbins E. A novel potassium channel in lymphocyte mitochondria. The Journal of biological chemistry. 2005; 280:12790-12798
26. Bednarczyk P, Kowalczyk JE, Beresewicz M, Dolowy K, Szewczyk A and Zablocka B. Identification of a voltage-gated potassium channel in gerbil hippocampal mitochondria. Biochemical and biophysical research communications. 2010; 397:614-620
27. Gulbins E, Sassi N, Grassme H, Zoratti M and Szabo I. Role of Kv1.3 mitochondrial potassium channel in apoptotic signalling in lymphocytes. Biochimica et biophysica acta. 2010; 1797:1251-1259
28. Leanza L, Henry B, Sassi N, Zoratti M, Chandy KG, Gulbins E and Szabo I. Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. EMBO molecular medicine. 2012; 4:577-593
29. Zhu J, Yan J and Thornhill WB. The Kv1.3 potassium channel is localized to the cis-Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes. The FEBS journal. 2014; 281:3433-3445
30. Jang SH, Byun JK, Jeon WI, Choi SY, Park J, Lee BH, Yang JE, Park JB, O'Grady SM, Kim DY, Ryu PD, Joo SW and Lee SY. Nuclear localization and functional characteristics of voltage-gated potassium channel Kv1.3. The Journal of biological chemistry. 2015; 290:12547-12557
31. Szabo I, Bock J, Grassme H, Soddemann M, Wilker B, Lang F, Zoratti M and Gulbins E. Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105:14861-14866
32. Szabo I, Soddemann M, Leanza L, Zoratti M and Gulbins E. Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax-and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosis. Cell death and differentiation. 2011; 18:427-438
33. Leanza L, Venturini E, Kadow S, Carpinteiro A, Gulbins E and Becker KA. Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium. 2014
34. Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J, Dang Y, Zhang J, Jiang H, Penner R and Liu JO. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PloS one. 2008; 3:e4009
35. Cholo MC, Steel HC, Fourie PB, Germishuizen WA and Anderson R. Clofazimine: current status and future prospects. The Journal of antimicrobial chemotherapy. 2012; 67:290-298
36. Pilarsky C, Wenzig M, Specht T, Saeger HD and Grutzmann R. Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia (New York, NY). 2004; 6:744-750
37. Grutzmann R, Pilarsky C, Ammerpohl O, Luttges J, Bohme A, Sipos B, Foerder M, Alldinger I, Jahnke B, Schackert HK, Kalthoff H, Kremer B, Kloppel G and Saeger HD. Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia (New York, NY). 2004; 6:611-622
38. Liu N, Furukawa T, Kobari M and Tsao MS. Comparative phenotypic studies of duct epithelial cell lines derived from normal human pancreas and pancreatic carcinoma. The American journal of pathology. 1998; 153:263-269
39. Ungefroren H, Voss M, Jansen M, Roeder C, Henne-Bruns D, Kremer B and Kalthoff H. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis. Cancer research. 1998; 58:1741-1749
40. Sipos B, Moser S, Kalthoff H, Torok V, Lohr M and Kloppel G. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Archiv. 2003; 442:444-452
41. Monti P, Marchesi F, Reni M, Mercalli A, Sordi V, Zerbi A, Balzano G, Di Carlo V, Allavena P and Piemonti L. A comprehensive in vitro characterization of pancreatic ductal carcinoma cell line biological behavior and its correlation with the structural and genetic profile. Virchows Archiv. 2004; 445:236-247
42. Hinz S, Trauzold A, Boenicke L, Sandberg C, Beckmann S, Bayer E, Walczak H, Kalthoff H and Ungefroren H. Bcl-XL protects pancreatic adenocarcinoma cells against CD95-and TRAIL-receptor-mediated apoptosis. Oncogene. 2000; 19:5477-5486
43. Zhou DH, Yang LN, Roder C, Kalthoff H and Trauzold A. TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells. Hepatobiliary & pancreatic diseases international. 2013; 12:94-98
44. Cohen R, Neuzillet C, Tijeras-Raballand A, Faivre S, de Gramont A and Raymond E. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget. 2015; 6:16832-16847. doi: 10.18632/oncotarget.4160
45. Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S, Kettler B, von Forstner C, Kneitz C, Tepel J, Adam D, Wajant H, Kalthoff H and Trauzold A. Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer research. 2008; 68:1443-1450
46. Nosengo N. Can you teach old drugs new tricks? Nature. 2016; 534:314-316
47. Robbins N, Spitzer M, Yu T, Cerone RP, Averette AK, Bahn YS, Heitman J, Sheppard DC, Tyers M and Wright GD. An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens. Cell reports. 2015; 13:1481-1492
48. Gogvadze V, Zhivotovsky B and Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Molecular aspects of medicine. 2010; 31:60-74
49. Gogvadze V. Targeting mitochondria in fighting cancer. Current pharmaceutical design. 2011; 17:4034-4046
50. Liu J and Wang Z. Increased Oxidative Stress as a Selective Anticancer Therapy. Oxidative medicine and cellular longevity. 2015; 2015:294303
51. Gorrini C, Harris IS and Mak TW. Modulation of oxidative stress as an anticancer strategy. Nature reviews Drug discovery. 2013; 12:931-947
52. Szabo I and Zoratti M. Mitochondrial channels: ion fluxes and more. Physiological reviews. 2014; 94:519-608
53. Lonardo E, Cioffi M, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, Balic A, Hidalgo M and Heeschen C. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PloS one. 2013; 8:e76518
54. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, et al. Oncogene ablationresistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014; 514:628-632
55. Koval AV, Vlasov P, Shichkova P, Khunderyakova S, Markov Y, Panchenko J, Volodina A, Kondrashov FA and Katanaev VL. Anti-leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling. Biochemical pharmacology. 2014; 87:571-578
56. Arensman MD, Nguyen P, Kershaw KM, Lay AR, Ostertag-Hill CA, Sherman MH, Downes M, Liddle C, Evans RM and Dawson DW. Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer. Molecular cancer research. 2015; 13:1509-1519
57. Morris JPt, Wang SC and Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nature reviews Cancer. 2010; 10:683-695
58. Van Rensburg CE, Anderson R, Myer MS, Joone GK and O'Sullivan JF. The riminophenazine agents clofazimine and B669 reverse acquired multidrug resistance in a human lung cancer cell line. Cancer letters. 1994; 85:59-63
59. Koot D and Cromarty D. Anticancer efficacy and toxicokinetics of a novel paclitaxel-clofazimine nanoparticulate co-formulation. Drug delivery and translational research. 2015; 5:257-267
60. Patil SP. FOLICation: engineering approved drugs as potential p53-MDM2 interaction inhibitors for cancer therapy. Medical hypotheses. 2013; 81:1104-1107
61. Casey FP, Pihan E and Shields DC. Discovery of small molecule inhibitors of protein-protein interactions using combined ligand and target score normalization. Journal of chemical information and modeling. 2009; 49:2708-2717
62. Ruff P, Chasen MR, Long JE and van Rensburg CE. A phase II study of oral clofazimine in unresectable and metastatic hepatocellular carcinoma. Annals of oncology. 1998; 9:217-219
63. Buckway B, Wang Y, Ray A and Ghandehari H. Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors. International journal of pharmaceutics. 2013; 456:202-211
64. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N and Tuveson DA. The pancreas cancer microenvironment. Clinical cancer research. 2012; 18:4266-4276
65. Nix DE, Adam RD, Auclair B, Krueger TS, Godo PG and Peloquin CA. Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberculosis (Edinburgh, Scotland). 2004; 84:365-373
66. Jadhav MV, Sathe AG, Deore SS, Patil PG and Joshi NG. Tissue concentration, systemic distribution and toxicity of clofazimine-an autopsy study. Indian journal of pathology & microbiology. 2004; 47:281-283
67. Yoon GS, Sud S, Keswani RK, Baik J, Standiford TJ, Stringer KA and Rosania GR. Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFalpha and Boosting IL-1RA Secretion. Molecular pharmaceutics. 2015; 12:2517-2527
68. Goumas FA, Holmer R, Egberts JH, Gontarewicz A, Heneweer C, Geisen U, Hauser C, Mende MM, Legler K, Rocken C, Becker T, Waetzig GH, Rose-John S and Kalthoff H. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. International journal of cancer. 2015; 137:1035-1046
69. Lastraioli E, Perrone G, Sette A, Fiore A, Crociani O, Manoli S, D'Amico M, Masselli M, Iorio J, Callea M, Borzomati D, Nappo G, Bartolozzi F, et al. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma. British journal of cancer. 2015; 112:1076-1087
70. Al-Wadei MH, Al-Wadei HA and Schuller HM. Gammaamino butyric acid (GABA) prevents the induction of nicotinic receptor-regulated signaling by chronic ethanol in pancreatic cancer cells and normal duct epithelia. Cancer prevention research (Philadelphia, Pa). 2013; 6:139-148
71. Rybarczyk P, Gautier M, Hague F, Dhennin-Duthille I, Chatelain D, Kerr-Conte J, Pattou F, Regimbeau JM, Sevestre H and Ouadid-Ahidouch H. Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration. International journal of cancer. 2012; 131:E851-861
72. Kondratska K, Kondratskyi A, Yassine M, Lemonnier L, Lepage G, Morabito A, Skryma R and Prevarskaya N. Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochimica et biophysica acta. 2014; 1843:2263-2269
73. Giannuzzo A, Pedersen SF and Novak I. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells. Molecular cancer. 2015; 14:203
74. Kong SC, Giannuzzo A, Novak I and Pedersen SF. Acidbase transport in pancreatic cancer: molecular mechanisms and clinical potential. Biochemistry and cell biology = Biochimie et biologie cellulaire. 2014; 92:449-459
75. Hoffmann EK and Lambert IH. Ion channels and transporters in the development of drug resistance in cancer cells. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2014; 369:20130109
76. Cardone RA, Greco MR, Zeeberg K, Zaccagnino A, Saccomano M, Bellizzi A, Bruns P, Menga M, Pilarsky C, Schwab A, Alves F, Kalthoff H, Casavola V and Reshkin SJ. A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy. Neoplasia (New York, NY). 2015; 17:155-166
77. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS and Kalluri R. Epithelialto-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015; 527:525-530
78. Morgan RT, Woods LK, Moore GE, Quinn LA, McGavran L and Gordon SG. Human cell line (COLO 357) of metastatic pancreatic adenocarcinoma. International journal of cancer. 1980; 25:591-598
79. Ouyang H, Mou L, Luk C, Liu N, Karaskova J, Squire J and Tsao MS. Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. The American journal of pathology. 2000; 157:1623-1631
80. Leanza L, O'Reilly P, Doyle A, Venturini E, Zoratti M, Szegezdi E and Szabo I. Correlation between potassium channel expression and sensitivity to drug-induced cell death in tumor cell lines. Current pharmaceutical design. 2014; 20:189-200
81. Leanza L, Zoratti M, Gulbins E and Szabo I. Induction of apoptosis in macrophages via Kv1.3 and Kv1.5 potassium channels. Current medicinal chemistry. 2012; 19:5394-5404
82. Tepel J, Dagvadorj O, Kapischke M, Sipos B, Leins A, Kremer B and Kalthoff H. Significant growth inhibition of orthotopic pancreatic ductal adenocarcinoma by CpG oligonucleotides in immunodeficient mice. International journal of colorectal disease. 2006; 21:365-372
83. Azzolini M, La Spina M, Mattarei A, Paradisi C, Zoratti M and Biasutto L. Pharmacokinetics and tissue distribution of pterostilbene in the rat. Molecular nutrition & food research. 2014; 58:2122-2132
84. Azzolini M, Mattarei A, La Spina M, Marotta E, Zoratti M, Paradisi C and Biasutto L. Synthesis and Evaluation as Prodrugs of Hydrophilic Carbamate Ester Analogues of Resveratrol. Molecular pharmaceutics. 2015; 12:3441-3454