Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies

European Journal of Pharmacology

Volumn 625, Issue 1-3, 2009, Pages 220-233

  Solomon, V Raja ^a,b   Lee, Hoyun ^a,b  

^a SUDBURY REGIONAL HOSPITAL   (Canada)

^b LAURENTIAN UNIVERSITY   (Canada)

Author keywords

4 Aminoquinoline; Anti malarial; Anti rheumatoid; Cancer therapeutics; Chemosensitizer; Chloroquine

Indexed keywords

2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; ACLARUBICIN; ANTINEOPLASTIC AGENT; CHLOROQUINE; CINCHONINE; CYCLOPHOSPHAMIDE; DNA TOPOISOMERASE INHIBITOR; DOXORUBICIN; ETOPOSIDE; HYDROXYCHLOROQUINE; IMATINIB; IMMUNOTOXIN; IMMUNOTOXIN TF CRM109; MITOXANTRONE; NSC 10010; NSC 305819; NSC 3852; NSC 69603; NSC 709257; NSC 86371; OMEPRAZOLE; PLACEBO; PROTEIN KINASE B INHIBITOR; QUINIDINE; QUININE; QUINOLONE DERIVATIVE; TAMOXIFEN; TENIPOSIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VORINOSTAT;

ANTIMALARIAL ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AUTOPHAGY; BRAIN TUMOR; BREAST CANCER; BURKITT LYMPHOMA; CANCER RADIOTHERAPY; CANCER THERAPY; CELL DIFFERENTIATION; CHRONIC MYELOID LEUKEMIA; CLINICAL PRACTICE; CLINICAL TRIAL; DNA FRAGMENTATION; DRUG CHOICE; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; DRUG SENSITIZATION; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; GLIOBLASTOMA; HEART ARRHYTHMIA; HUMAN; IONIZING RADIATION; LIVER AMEBIASIS; LUNG CANCER; LUNG SMALL CELL CANCER; LUPUS ERYTHEMATOSUS; LYMPHOMA; MALARIA; MALARIA FALCIPARUM; MULTIPLE MYELOMA; NONHUMAN; OVARY CANCER; PHYSICAL CHEMISTRY; PLASMACYTOMA; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; RHEUMATOID ARTHRITIS; SOLID TUMOR;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; AUTOPHAGY; CHLOROQUINE; DRUG SYNERGISM; HUMANS; NEOPLASMS; RADIATION, IONIZING;

EID: 71749096160     PISSN: 00142999     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ejphar.2009.06.063     Document Type: Review

References (176)

1. Abrams J.S., Moore T.D., and Friedman M. New chemotherapeutic agents for breast cancer. Cancer 74 (1994) 1164-1176
2. Aderem A., and Underhill D.M. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17 (1999) 593-623
3. Amaravadi R.K., Yu D., Lum J.J., Bui T., Christophorou M.A., Evan G.I., Thomas-Tikhonenko A., and Thompson C.B. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117 (2007) 326-336
4. Andersag H., Breitner S., and Jung H. Quinoline compound and process of making the same. German Pat. 683 692. Chem. Abstr. 36 (1942) 4973
5. Augustijns P., Geusens P., and Verbeke N. Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis. Eur. J. Clin. Pharmacol. 42 (1992) 429-433
6. Beardsley D.I., Kim W.J., and Brown K.D. N-methyl-N′-nitro-N-nitrosoguanidine activates cell-cycle arrest through distinct mechanisms activated in a dose-dependent manner. Mol. Pharmacol. 68 (2005) 1049-1060
7. Beierwaltes W.H., Varma V.M., Counsell R.E., and Lieberman L.M. Scintillation scanning of malignant melanomas with radioiodinated quinoline derivatives. J. Nucl. Med. 9 (1968) 489-491
8. Bissonnette R.P., Echeverri F., Mahboubi A., and Green D.R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359 (1992) 552-554
9. Bonadonna G. Current and future trends in the multidisciplinary approach for high-risk breast cancer. The experience of the Milan Cancer Institute. Eur. J. Cancer 32A (1996) 209-214
10. Borgonovo B., Cocucci E., Racchetti G., Podini P., Bachi A., and Meldolesi J. Regulated exocytosis: a novel, widely expressed system. Nat. Cell Biol. 4 (2002) 955-962
11. Bork E., Ersboll J., Dombernowsky P., Bergman B., Hansen M., and Hansen H.H. Teniposide and etoposide in previously untreated small-cell lung cancer: a randomized study. J. Clin. Oncol. 9 (1991) 1627-1631
12. Boya P., Gonzalez-Polo R.A., Poncet D., Andreau K., Vieira H.L., Roumier T., Perfettini J.L., and Kroemer G. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 22 (2003) 3927-3936
13. Boyer M.J., and Tannock I.F. Regulation of intracellular pH in tumor cell lines: influence of microenvironmental conditions. Cancer Res. 52 (1992) 4441-4447
14. Breckenridge A.M., and Winstanley P.A. Clinical pharmacology and malaria. Ann. Trop. Med. Parasitol. 91 (1997) 727-733
15. Briceno E., Reyes S., and Sotelo J. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg. Focus 14 (2003) e3
16. Briceno E., Calderon A., and Sotelo J. Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg. Neurol. 67 (2007) 388-391
17. Brown J.M. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol. Med. Today 6 (2000) 157-162
18. Butler D., Brown Q.B., Chin D.J., Batey L., Karim S., Mutneja M.S., Karanian D.A., and Bahr B.A. Cellular responses to protein accumulation involve autophagy and lysosomal enzyme activation. Rejuvenation Res. 8 (2005) 227-237
19. Carew J.S., Nawrocki S.T., Krupnik Y.V., Dunner Jr. K., McConkey D.J., Keating M.J., and Huang P. Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL. Blood 107 (2006) 222-231
20. Chatterjee T., Muhkopadhyay A., Khan K.A., and Giri A.K. Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine. Mutagenesis 13 (1998) 619-624
21. Chau I., and Cunningham D. Adjuvant therapy in colon cancer - what, when and how?. Ann. Oncol. 17 (2006) 1347-1359
22. Cheng G.Z., Park S., Shu S., He L., Kong W., Zhang W., Yuan Z., Wang L.H., and Cheng J.Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets 8 (2008) 2-6
23. Chibale K., Ojima I., Haupt H., Geng X., Pera P., and Bernacki R.J. Modulation of human mammary cell sensitivity to paclitaxel by new quinoline sulfonamides. Bioorg. Med. Chem. Lett. 11 (2001) 2457-2460
24. Cho J., and Rando R.R. Specific binding of Hoechst 33258 to site 1 thymidylate synthase mRNA. Nucleic Acids Res. 28 (2000) 2158-2163
25. Chong C.R., and Sullivan Jr. D.J. New uses for old drugs. Nature 448 (2007) 645-646
26. Coatney G.R., Cooper W.C., and Ruhe D.S. Studies in human malaria; the organization of a program for testing potential antimalarial drugs in prisoner volunteers. Am. J. Hyg. 47 (1948) 113-119
27. Conan N.J. The treatment of amebic hepatitis with chloroquine. Bull. N.Y. Acad. Med. 24 (1948) 545-546
28. Cuervo A.M. Autophagy: in sickness and in health. Trends Cell Biol. 14 (2004) 70-77
29. Cuervo A.M. Autophagy and aging: keeping that old broom working. Trends Genet. 24 (2008) 604-612
30. Dai Y., Rahmani M., Dent P., and Grant S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol. Cell. Biol. 25 (2005) 5429-5444
31. Dalpke A.H., Opper S., Zimmermann S., and Heeg K. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J. Immunol. 166 (2001) 7082-7089
32. Degtyarev M., De M.A., Orr C., Lin J., Lee B.B., Tien J.Y., Prior W.W., Van D.S., Wu H., Gray D.C., Davis D.P., Stern H.M., Murray L.J., Hoeflich K.P., Klumperman J., Friedman L.S., and Lin K. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J. Cell Biol. 183 (2008) 101-116
33. DiMasi J.A., Hansen R.W., and Grabowski H.G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22 (2003) 151-185
34. Dorn A., Stoffel R., Matile H., Bubendorf A., and Ridley R.G. Malarial haemozoin/beta-haematin supports haem polymerization in the absence of protein. Nature 374 (1995) 269-271
35. Erikson E., Haystead T.A., Qian Y.W., and Maller J.L. A feedback loop in the polo-like kinase activation pathway. J. Biol. Chem. 279 (2004) 32219-32224
36. Evan G.I., and Vousden K.H. Proliferation, cell cycle and apoptosis in cancer. Nature 411 (2001) 342-348
37. Fader C.M., Savina A., Sanchez D., and Colombo M.I. Exosome secretion and red cell maturation: exploring molecular components involved in the docking and fusion of multivesicular bodies in K562 cells. Blood Cells Mol. Dis. 35 (2005) 153-157
38. Fader C.M., Sanchez D., Furlan M., and Colombo M.I. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic 9 (2008) 230-250
39. Faivre S., Djelloul S., and Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin. Oncol. 33 (2006) 407-420
40. Fan C., Wang W., Zhao B., Zhang S., and Miao J. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells. Bioorg. Med. Chem. 14 (2006) 3218-3222
41. Fanidi A., Harrington E.A., and Evan G.I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 359 (1992) 554-556
42. Field R.C., Gibson B.R., Holbrook Jr. D.J., and McCall B.M. Inhibition of precursor incorporation into nucleic acids of mammalian tissues by antimalarial aminoquinolines. Br. J. Pharmacol. 62 (1978) 159-164
43. 2+-antagonistic properties of phospholipase A2 inhibitors, mepacrine and chloroquine. Gen. Physiol. Biophys. 8 (1989) 113-118
44. Giampietri A., Fioretti M.C., Goldin A., and Bonmassar E. Drug-mediated antigenic changes in murine leukemia cells: antagonistic effects of quinacrine, an antimutagenic compound. J. Natl. Cancer Inst. 64 (1980) 297-301
45. Glaumann H., and Ahlberg J. Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity-formation of crinosomes. Exp. Mol. Pathol. 47 (1987) 346-362
46. Goldsworthy T.L., Conolly R.B., and Fransson-Steen R. Apoptosis and cancer risk assessment. Mutat. Res. 365 (1996) 71-90
47. Green D.R., and Reed J.C. Mitochondria and apoptosis. Science 281 (1998) 1309-1312
48. Greenfield L., Johnson V.G., and Youle R.J. Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science 238 (1987) 536-539
49. Greenwood D. Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war. J. Antimicrob. Chemother. 36 (1995) 857-872
50. Guttmann P., and Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. Berl. Klin. Wochenschr. 28 (1891) 953
51. Hagihara N., Walbridge S., Olson A.W., Oldfield E.H., and Youle R.J. Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107. Cancer Res. 60 (2000) 230-234
52. Haworth S., Lawlor T., Mortelmans K., Speck W., and Zeiger E. Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen. 5 Suppl 1 (1983) 1-142
53. Hennig R., Ding X.Z., Tong W.G., Witt R.C., Jovanovic B.D., and Adrian T.E. Effect of LY293111 in combination with gemcitabine in colonic cancer. Cancer Lett. 210 (2004) 41-46
54. Hofheinz W., and Merkli B. Quinine and quinine analogues. In: Peters W., and Richards W.H.G. (Eds) (1984), Springer Verlag, Berlin 61-81
55. Hosoya Y., Kitoh Y., Kobayashi E., Okabe R., Fujimura A., and Kanazawa K. Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines in vitro. Cancer Lett. 140 (1999) 139-143
56. Hostetler K.Y., Reasor M., and Yazaki P.J. Chloroquine-induced phospholipid fatty liver. Measurement of drug and lipid concentrations in rat liver lysosomes. J. Biol. Chem. 260 (1985) 215-219
57. Hu C., Solomon V.R., Ulibarri G., and Lee H. The efficacy and selectivity of tumor cell killing by Akt inhibitors are substantially increased by chloroquine. Bioorg. Med. Chem. 16 (2008) 7888-7893
58. Hurwitz S.J., Terashima M., Mizunuma N., and Slapak C.A. Vesicular anthracycline accumulation in doxorubicin-selected U-937 cells: participation of lysosomes. Blood 89 (1997) 3745-3754
59. Inaba M., and Maruyama E. Reversal of resistance to vincristine in P388 leukemia by various polycyclic clinical drugs, with a special emphasis on quinacrine. Cancer Res. 48 (1988) 2064-2067
60. Jensen P.B., Sorensen B.S., Sehested M., Grue P., Demant E.J., and Hansen H.H. Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments. Cancer Res. 54 (1994) 2959-2963
61. Jiang P.D., Zhao Y.L., Shi W., Deng X.Q., Xie G., Mao Y.Q., Li Z.G., Zheng Y.Z., Yang S.Y., and Wei Y.Q. Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37. Cell. Physiol. Biochem. 22 (2008) 431-440
62. Johnson V.G., Wilson D., Greenfield L., and Youle R.J. The role of the diphtheria toxin receptor in cytosol translocation. J. Biol. Chem. 263 (1988) 1295-1300
63. Karres I., Kremer J.P., Dietl I., Steckholzer U., Jochum M., and Ertel W. Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am. J. Physiol. 274 (1998) R1058-R1064
64. Kaufman T.S., and Ruveda E.A. The quest for quinine: those who won the battles and those who won the war. Angew. Chem. Int. Ed. Engl. 44 (2005) 854-885
65. Kerr J.F., Wyllie A.H., and Currie A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26 (1972) 239-257
66. Kim S.H., Kim J.H., and Fried J. Enhancement of the radiation response of cultured tumor cells by chloroquine. Cancer 32 (1973) 536-540
67. Kondo Y., Kanzawa T., Sawaya R., and Kondo S. The role of autophagy in cancer development and response to therapy. Nat. Rev., Cancer 5 (2005) 726-734
68. Krajewski S., Krajewska M., Turner B.C., Pratt C., Howard B., Zapata J.M., Frenkel V., Robertson S., Ionov Y., Yamamoto H., Perucho M., Takayama S., and Reed J.C. Prognostic significance of apoptosis regulators in breast cancer. Endocr.-Relat. Cancer 6 (1999) 29-40
69. Kroemer G., and Jaattela M. Lysosomes and autophagy in cell death control. Nat. Rev., Cancer 5 (2005) 886-897
70. Kunze H., Hesse B., and Bohn E. Effects of antimalarial drugs on several rat-liver lysosomal enzymes involved in phosphatidylethanolamine catabolism. Biochim. Biophys. Acta 713 (1982) 112-117
71. Laske D.W., Ilercil O., Akbasak A., Youle R.J., and Oldfield E.H. Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J. Neurosurg. 80 (1994) 520-526
72. Laske D.W., Youle R.J., and Oldfield E.H. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat. Med. 3 (1997) 1362-1368
73. Law P.Y., Hom D.S., and Loh H.H. Down-regulation of opiate receptor in neuroblastoma x glioma NG108-15 hybrid cells. Chloroquine promotes accumulation of tritiated enkephalin in the lysosomes. J. Biol. Chem. 259 (1984) 4096-4104
74. Lee C.M., and Tannock I.F. Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration. Br. J. Cancer 94 (2006) 863-869
75. Leppla S., Dorland R.B., and Middlebrook J.L. Inhibition of diphtheria toxin degradation and cytotoxic action by chloroquine. J. Biol. Chem. 255 (1980) 2247-2250
76. Levine B., and Yuan J. Autophagy in cell death: an innocent convict?. J. Clin. Invest. 115 (2005) 2679-2688
77. Lieberman L.M., Boyd C.M., Varma V.M., Bergstrom T.J., and Beierwaltes W.H. Treatment doses of 131-I-labeled chloroquine analog in normal and malignant melanoma dogs. J. Nucl. Med. 12 (1971) 153-159
78. Lockshin R.A., and Zakeri Z. Apoptosis, autophagy, and more. Int. J. Biochem. Cell Biol. 36 (2004) 2405-2419
79. Loeb R.F., Clark W.M., Coatney G.R., Coggeshall L.T., Dieuaide F.R., Dochez A.R., Hakansson E.G., Marshall E.K., Marvel S.C., McCoy O.R., Sapero J.J., Sebrell W.H., Shannon J.A., and Carden G.A. Activity of a new antimalarial agent, chloroquine (SN7618). J. Am. Med. Assoc. 130 (1946) 1069-1070
80. Loehberg C.R., Thompson T., Kastan M.B., Maclean K.H., Edwards D.G., Kittrell F.S., Medina D., Conneely O.M., and O'Malley B.W. Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res. 67 (2007) 12026-12033
81. Lowe S.W., Cepero E., and Evan G. Intrinsic tumour suppression. Nature 432 (2004) 307-315
82. Lu Z., Luo R.Z., Peng H., Rosen D.G., Atkinson E.N., Warneke C., Huang M., Nishmoto A., Liu J., Liao W.S., Yu Y., and Bast Jr. R.C. Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Clin. Cancer Res. 12 (2006) 2404-2413
83. Lu Z., Luo R.Z., Lu Y., Zhang X., Yu Q., Khare S., Kondo S., Kondo Y., Yu Y., Mills G.B., Liao W.S., and Bast Jr. R.C. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J. Clin. Invest. 118 (2008) 3917-3929
84. Luo R.Z., Peng H., Xu F., Bao J., Pang Y., Pershad R., Issa J.P., Liao W.S., Bast Jr. R.C., and Yu Y. Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI. Biochim. Biophys. Acta 1519 (2001) 216-222
85. Maclean K.H., Dorsey F.C., Cleveland J.L., and Kastan M.B. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin. Invest. 118 (2008) 79-88
86. Majno G., and Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146 (1995) 3-15
87. Martirosyan A., Leonard S., Shi X., Griffith B., Gannett P., and Strobl J. Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells. J. Pharmacol. Exp. Ther. 317 (2006) 546-552
88. Mayer L.D., Bally M.B., and Cullis P.R. Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient. Biochim. Biophys. Acta 857 (1986) 123-126
89. McNeil C.M., Sergio C.M., Anderson L.R., Inman C.K., Eggleton S.A., Murphy N.C., Millar E.K., Crea P., Kench J.G., Alles M.C., Gardiner-Garden M., Ormandy C.J., Butt A.J., Henshall S.M., Musgrove E.A., and Sutherland R.L. c-Myc overexpression and endocrine resistance in breast cancer. J. Steroid Biochem. Mol. Biol. 102 (2006) 147-155
90. Meinao I.M., Sato E.I., Andrade L.E., Ferraz M.B., and Atra E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 5 (1996) 237-241
91. Melkoumian Z.K., Martirosyan A.R., and Strobl J.S. Myc protein is differentially sensitive to quinidine in tumor versus immortalized breast epithelial cell lines. Int. J. Cancer 102 (2002) 60-69
92. Meshnick S.R., and Dobson M.J. In: Rosenthal P.J. (Ed). Antimalarial Chemotherapy (2001), Humana Press, Totowa, New Jersey 15-25
93. Michael R.O., and Williams G.M. Chloroquine inhibition of repair of DNA damage induced in mammalian cells by methyl methanesulfonate. Mutat. Res. 25 (1974) 391-396
94. Mishima Y., Terui Y., Mishima Y., Taniyama A., Kuniyoshi R., Takizawa T., Kimura S., Ozawa K., and Hatake K. Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors. Cancer Sci. 99 (2008) 2200-2208
95. Munster P.N., Troso-Sandoval T., Rosen N., Rifkind R., Marks P.A., and Richon V.M. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 61 (2001) 8492-8497
96. Newell K., Franchi A., Pouyssegur J., and Tannock I. Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc. Natl. Acad. Sci. U. S. A. 90 (1993) 1127-1131
97. Nosal R., and Jancinova V. Cationic amphiphilic drugs and platelet phospholipase A(2) (cPLA(2)). Thromb. Res. 105 (2002) 339-345
98. Nyati M.K., Feng F.Y., Kanade V.D., and Nayak R. Chloroquine treatment increases detection of 5-fluorouracil-induced apoptosis index in vivo. Mol. Imaging 5 (2006) 148-152
99. O'Brien R.L., Allison J.L., and Hahn F.E. Evidence for intercalation of chloroquine into DNA. Biochim. Biophys. Acta 129 (1966) 622-624
100. Ocana A., Cruz J.J., and Pandiella A. Trastuzumab and antiestrogen therapy: focus on mechanisms of action and resistance. Am. J. Clin. Oncol. 29 (2006) 90-95
101. O'Connor O.A., Heaney M.L., Schwartz L., Richardson S., Willim R., Gregor- Cortelli B., Curly T., Moskowitz C., Portlock C., Horwitz S., Zelenetz A.D., Frankel S., Richon V., Marks P., and Kelly W.K. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 24 (2006) 166-173
102. Paludan C., Schmid D., Landthaler M., Vockerodt M., Kube D., Tuschl T., and Munz C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307 (2005) 593-596
103. Pandey A.V., Bisht H., Babbarwal V.K., Srivastava J., Pandey K.C., and Chauhan V.S. Mechanism of malarial haem detoxification inhibition by chloroquine. Biochem. J. 355 (2001) 333-338
104. Papadopoulou M.V., Ji M., and Bloomer W.D. NLCQ-1, a novel hypoxic cytotoxin: potentiation of melphalan, cisDDP and cyclophosphamide in vivo. Int. J. Radiat. Oncol. Biol. Phys. 42 (1998) 775-779
105. Papadopoulou M.V., Ji M., Rao M.K., and Bloomer W.D. 4-[3-(2-Nitro-1- imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive compound as a hypoxia-selective cytotoxin. Oncol. Res. 12 (2000) 185-192
106. Papadopoulou M.V., Ji M., and Bloomer W.D. Schedule-dependent potentiation of chemotherapeutic drugs by the bioreductive compounds NLCQ-1 and tirapazamine against EMT6 tumors in mice. Cancer Chemother. Pharmacol. 48 (2001) 160-168
107. Papadopoulou M.V., Ji M., Bloomer W.D., and Hollingshead M.G. Enhancement of the antitumor effect of cyclophosphamide with the hypoxia-selective cytotoxin NLCQ-1 against murine tumors and human xenografts. J. Exp. Ther. Oncol. 2 (2002) 298-305
108. Papadopoulou M.V., Ji M., Ji X., and Bloomer W.D. Therapeutic advantage from combining 5-fluorouracil with the hypoxia-selective cytotoxin NLCQ-1 in vivo; comparison with tirapazamine. Cancer Chemother. Pharmacol. 50 (2002) 291-298
109. Papadopoulou M.V., Ji M., Ji X., Bloomer W.D., and Hollingshead M.G. Therapeutic advantage from combining paclitaxel with the hypoxia-selective cytotoxin NLCQ-1 in murine tumor- or human xenograft-bearing mice. Cancer Chemother. Pharmacol. 50 (2002) 501-508
110. Papadopoulou M.V., Ji M., and Bloomer W.D. Synergistic enhancement of the antitumor effect of taxol by the bioreductive compound NLCQ-1, in vivo: comparison with tirapazamine. Oncol. Res. 13 (2002) 47-54
111. Papadopoulou M.V., Ji M., Rao M.K., and Bloomer W.D. Reductive metabolism of the nitroimidazole-based hypoxia-selective cytotoxin NLCQ-1 (NSC 709257). Oncol. Res. 14 (2003) 21-29
112. Park J., Choi K., Jeong E., Kwon D., Benveniste E.N., and Choi C. Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia 47 (2004) 9-20
113. Pelletier P.J., and Caventou C.B. Des Recherches chimiques sur les Quinguinas. Ann. Chim. Phys. 15 (1820) 337
114. Pharoah P.D., Day N.E., and Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br. J. Cancer 80 (1999) 1968-1973
115. Phillips R.M., Loadman P.M., and Cronin B.P. Evaluation of a novel in vitro assay for assessing drug penetration into a vascular regions of tumours. Br. J. Cancer 77 (1998) 2112-2119
116. Poole B., and Ohkuma S. Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J. Cell Biol. 90 (1981) 665-669
117. Qu X., Yu J., Bhagat G., Furuya N., Hibshoosh H., Troxel A., Rosen J., Eskelinen E.L., Mizushima N., Ohsumi Y., Cattoretti G., and Levine B. Promotion of tumorigenesis by heterozygous disruption of the beclin-1 autophagy gene. J. Clin. Invest. 112 (2003) 1809-1820
118. Rajapakse C.S., Martinez A., Naoulou B., Jarzecki A.A., Suarez L., Deregnaucourt C., Sinou V., Schrevel J., Musi E., Ambrosini G., Schwartz G.K., and Sanchez- Delgado R.A. Synthesis, characterization, and in vitro antimalarial and antitumor activity of new ruthenium(II) complexes of chloroquine. Inorg. Chem. 48 (2009) 1122-1131
119. Reagan-Shaw S., and Ahmad N. Silencing of polo-like kinase (Plk) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer. FASEB J. 19 (2005) 611-613
120. Renwick A., Thompson D., Seal S., Kelly P., Chagtai T., Ahmed M., North B., Jayatilake H., Barfoot R., Spanova K., McGuffog L., Evans D.G., Eccles D., Easton D.F., Stratton M.R., and Rahman N. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38 (2006) 873-875
121. Reyes S., Herrera L.A., Ostrosky P., and Sotelo J. Quinacrine enhances carmustine therapy of experimental rat glioma. Neurosurgery 49 (2001) 969-973
122. Rosales-Hernandez M.C., Bermudez-Lugo J., Garcia J., Trujillo-Ferrara J., and Correa- Basurto J. Molecular modeling applied to anti-cancer drug development. Anticancer Agents Med. Chem. 9 (2009) 230-238
123. Rosato R.R., Almenara J.A., and Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1. Cancer Res. 63 (2003) 3637-3645
124. Rosato R.R., Maggio S.C., Almenara J.A., Payne S.G., Atadja P., Spiegel S., Dent P., and Grant S. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol. Pharmacol. 69 (2006) 216-225
125. Rosen D.G., Yang G., Liu G., Mercado-Uribe I., Chang B., Xiao X.S., Zheng J., Xue F.X., and Liu J. Ovarian cancer: pathology, biology, and disease models. Front. Biosci. 14 (2009) 2089-2102
126. Samuels Y., and Ericson K. Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol. 18 (2006) 77-82
127. Sartorius J., and Schneider H.J. Interclation mechanisms with s-DNA: binding modes and energy contributions with benzene, naphthalene, quinoline and indole derivatives including some antimalarials. J. Chem. Soc., Perkin Tans. 2: Phys. Org. Chem. 11 (1997) 2319-2328
128. Savarino A., Boelaert J.R., Cassone A., Majori G., and Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases?. Lancet, Infect. Dis. 3 (2003) 722-727
129. Savarino A., Di T.L., Donatelli I., Cauda R., and Cassone A. New insights into the antiviral effects of chloroquine. Lancet, Infect. Dis. 6 (2006) 67-69
130. Savarino A., Cauda R., and Cassone A. On the use of chloroquine for chikungunya. Lancet, Infect. Dis. 7 (2007) 633
131. Sax J.K., and El-Deiry W.S. p53 downstream targets and chemosensitivity. Cell Death Differ. 10 (2003) 413-417
132. Schindler M., Grabski S., Hoff E., and Simon S.M. Defective pH regulation of acidic compartments in human breast cancer cells (MCF-7) is normalized in adriamycin-resistant cells (MCF-7adr). Biochemistry 35 (1996) 2811-2817
133. Schlitzer M. Malaria chemotherapeutics part I: history of antimalarial drug development, currently used therapeutics, and drugs in clinical development. Chem. Med. Chem. 2 (2007) 944-986
134. Sehested M., Jensen P.B., Sorensen B.S., Holm B., Friche E., and Demant E.J. Antagonistic effect of the cardioprotector (+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16). Biochem. Pharmacol. 46 (1993) 389-393
135. Shacka J.J., Klocke B.J., Shibata M., Uchiyama Y., Datta G., Schmidt R.E., and Roth K.A. Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol. Pharmacol. 69 (2006) 1125-1136
136. Sivaraman L., and Medina D. Hormone-induced protection against breast cancer. J. Mammary Gland Biol. Neoplasia 7 (2002) 77-92
137. Sivaraman L., Stephens L.C., Markaverich B.M., Clark J.A., Krnacik S., Conneely O.M., O'Malley B.W., and Medina D. Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis 19 (1998) 1573-1581
138. Sivaraman L., Conneely O.M., Medina D., and O'Malley B.W. p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 12379-12384
139. Snyder R.D. Use of catalytic topoisomerase II inhibitors to probe mechanisms of chemical-induced clastogenicity in Chinese hamster V79 cells. Environ. Mol. Mutagen. 35 (2000) 13-21
140. Solary E., Bertrand R., and Pommier Y. Apoptosis induced by DNA topoisomerase I and II inhibitors in human leukemic HL-60 cells. Leuk. Lymphoma 15 (1994) 21-32
141. Sorensen M., Sehested M., and Jensen P.B. pH-dependent regulation of camptothecin-induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquine. Biochem. Pharmacol. 54 (1997) 373-380
142. Sotelo J., Briceno E., and Lopez-Gonzalez M.A. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 144 (2006) 337-343
143. Stambolic V., and Woodgett J.R. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol. 16 (2006) 461-466
144. Sternglanz H., Yielding K.L., and Pruitt K.M. Nuclear magnetic resonance studies of the interaction of chloroquine diphosphate with adenosine 5′-phosphate and other nucleotides. Mol. Pharmacol. 5 (1969) 376-381
145. Stocks P.A., Raynes K.J., and Ward S.A. Novel quinoline antimalarials. In: Rosentha P.J. (Ed). Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery (2001), Humana, Totowa 235-253
146. Sullivan Jr. D.J., Gluzman I.Y., Russell D.G., and Goldberg D.E. On the molecular mechanism of chloroquine's antimalarial action. Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 11865-11870
147. Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., Goodlett D.R., Aebersold R., Siderovski D.P., Penninger J.M., and Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397 (1999) 441-446
148. Suzuki T., Fukazawa N., San-nohe K., Sato W., Yano O., and Tsuruo T. Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer. J. Med. Chem. 40 (1997) 2047-2052
149. Tannock I.F., Lee C.M., Tunggal J.K., Cowan D.S., and Egorin M.J. Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clin. Cancer Res. 8 (2002) 878-884
150. Thompson C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267 (1995) 1456-1462
151. Thomsen A., and Kolesar J.M. Chemoprevention of breast cancer. Am. J. Health Syst. Pharm. 65 (2008) 2221-2228
152. Titus E.O. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther. Drug Monit. 11 (1989) 369-379
153. Turner R.B., and Woodward R.B. The chemistry of the cinchona. In: Manske R.H.F. (Ed). The Alkaloids (1953), Academic Press, New York 181-223
154. Vaupel P., Kallinowski F., and Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49 (1989) 6449-6465
155. Volkl H., Friedrich F., Haussinger D., and Lang F. Effect of cell volume on Acridine Orange fluorescence in hepatocytes. Biochem. J. 295 (1993) 11-14
156. Walenta S., Schroeder T., and Mueller-Klieser W. Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr. Med. Chem. 11 (2004) 2195-2204
157. Wang S., Melkoumian Z., Woodfork K.A., Cather C., Davidson A.G., Wonderlin W.F., and Strobl J.S. Evidence for an early G1 ionic event necessary for cell cycle progression and survival in the MCF-7 human breast carcinoma cell line. J. Cell. Physiol. 176 (1998) 456-464
158. Wang L., Hoque A., Luo R.Z., Yuan J., Lu Z., Nishimoto A., Liu J., Sahin A.A., Lippman S.M., Bast Jr. R.C., and Yu Y. Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin. Cancer Res. 9 (2003) 3660-3666
159. Waring M. Variation of the supercoils in closed circular DNA by binding of antibiotics and drugs: evidence for molecular models involving intercalation. J. Mol. Biol. 54 (1970) 247-279
160. Weber S.M., and Levitz S.M. Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism. J. Immunol. 165 (2000) 1534-1540
161. Wei M.C., Zong W.X., Cheng E.H., Lindsten T., Panoutsakopoulou V., Ross A.J., Roth K.A., MacGregor G.R., Thompson C.B., and Korsmeyer S.J. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292 (2001) 727-730
162. Wiesner J., Ortmann R., Jomaa H., and Schlitzer M. New antimalarial drugs. Angew. Chem. Int. Ed. Engl. 42 (2003) 5274-5293
163. Woodfork K.A., Wonderlin W.F., Peterson V.A., and Strobl J.S. Inhibition of ATP- sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture. J. Cell. Physiol. 162 (1995) 163-171
164. Woodward R.B., and Doering W.E. The total synthesis of quinine. J. Am. Chem. Soc. 66 (1944) 849-849
165. Yang S., Zhou Q., and Yang X. Caspase-3 status is a determinant of the differential responses to genistein between MDA-MB-231 and MCF-7 breast cancer cells. Biochim. Biophys. Acta 1773 (2007) 903-911
166. Yin F., Guo M., and Yao S. Kinetics of DNA binding with chloroquine phosphate using capacitive sensing method. Biosens. Bioelectron. 19 (2003) 297-304
167. Yu C., Subler M., Rahmani M., Reese E., Krystal G., Conrad D., Dent P., and Grant S. Induction of apoptosis in BCR/ABL+ cells by histone deacetylase inhibitors involves reciprocal effects on the RAF/MEK/ERK and JNK pathways. Cancer Biol. Ther. 2 (2003) 544-551
168. Yu L., Alva A., Su H., Dutt P., Freundt E., Welsh S., Baehrecke E.H., and Lenardo M.J. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304 (2004) 1500-1502
169. Zamora J.M., and Beck W.T. Chloroquine enhancement of anticancer drug cytotoxicity in multiple drug resistant human leukemic cells. Biochem. Pharmacol. 35 (1986) 4303-4310
170. Zamora J.M., Pearce H.L., and Beck W.T. Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol. Pharmacol. 33 (1988) 454-462
171. Zamzami N., Susin S.A., Marchetti P., Hirsch T., Gomez-Monterrey I., Castedo M., and Kroemer G. Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183 (1996) 1533-1544
172. Zhang H., Solomon V.R., Hu C., Ulibarri G., and Lee H. Synthesis and in vitro cytotoxicity evaluation of 4-aminoquinoline derivatives. Biomed. Pharmacother. 62 (2008) 65-69
173. Zhao H., Cai Y., Santi S., Lafrenie R., and Lee H. Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of cell death by necrosis. Radiat. Res. 164 (2005) 250-257
174. Zheng Y., Zhao Y.L., Deng X., Yang S., Mao Y., Li Z., Jiang P., Zhao X., and Wei Y. Chloroquine Inhibits Colon Cancer Cell Growth In Vitro and Tumor Growth In Vivo via Induction of Apoptosis. Cancer Invest. 27 (2009) 286-292
175. Zhou Q., Melkoumian Z.K., Lucktong A., Moniwa M., Davie J.R., and Strobl J.S. Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. J. Biol. Chem. 275 (2000) 35256-35263
176. Zhou Q., McCracken M.A., and Strobl J.S. Control of mammary tumor cell growth in vitro by novel cell differentiation and apoptosis agents. Breast Cancer Res. Treat. 75 (2002) 107-117