A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers

Journal of Medicinal Chemistry

Volumn 56, Issue 22, 2013, Pages 9170-9179

  Millard, Melissa ^a   Gallagher, John D ^a   Olenyuk, Bogdan Z ^a   Neamati, Nouri ^a,b  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHLORAMBUCIL; DIHYDROXY MITO CHLOR; MITO CHLOR; PHOSPHONIUM DERIVATIVE; TRIBUTYL MITO CHLOR; TRICYCLOHEXYL MITO CHLOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CANCER CHEMOTHERAPY; CELL CYCLE ARREST; CELL DEATH; CLINICAL EVALUATION; CONTROLLED STUDY; DRUG CONJUGATION; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG EFFECT; DRUG SAFETY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; HUMAN; HUMAN CELL; IC 50; MITOCHONDRIAL MEMBRANE POTENTIAL; MOUSE; NONHUMAN; PANCREAS CANCER; TUMOR CELL LINE; TUMOR VOLUME;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL TRANSPORT; BREAST NEOPLASMS; CELL PROLIFERATION; CHLORAMBUCIL; DNA BREAKS, DOUBLE-STRANDED; DNA, MITOCHONDRIAL; DRUG RESISTANCE, NEOPLASM; HISTONES; HUMANS; MICE; MITOCHONDRIA; PANCREATIC NEOPLASMS; PHOSPHORYLATION; REACTIVE OXYGEN SPECIES; S PHASE CELL CYCLE CHECKPOINTS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84889241501     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4012438     Document Type: Article

References (67)

1. Chabner, B. A., Bertino, J., Cleary, J., Ortiz, T., Lane, A., Supko, J. G., and Ryan, D. Cytotoxic Agents. In Goodman & Gilman's Pharmacologic Basis of Therapeutics:, 12th ed.; Brunton, L. L., C., B., and Knollmann, B. C., Ed.; McGraw-Hill: New York, 2011; Chapter 61.
2. Kohn, K. W. Molecular Aspects of Anti-Cancer Drug Action; Macmillan Publishers: London, 1980; pp 233-282.
3. Kohn, K. W.; Hartley, J. A.; Mattes, W. B. Mechanisms of DNA sequence selective alkylation of guanine-N7 positions by nitrogen mustards Nucleic Acids Res. 1987, 15, 10531-10549
4. Hemminki, K.; Ludlum, D. B. Covalent modification of DNA by antineoplastic agents J. Natl. Cancer Inst. 1984, 73, 1021-1028 (Pubitemid 15216192)
5. Hansson, J.; Lewensohn, R.; Ringborg, U.; Nilsson, B. Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells Cancer Res. 1987, 47, 2631-2637 (Pubitemid 17083153)
6. Panasci, L.; Paiement, J.-P.; Christodoulopoulos, G.; Belenkov, A.; Malapetsa, A.; Aloyz, R. Chlorambucil drug resistance in chronic lymphocytic leukemia Clin. Cancer Res. 2001, 7, 454-461
7. Catovsky, D.; Else, M.; Richards, S. Chlorambucil-still not bad: a reappraisal Clin. Lymphoma Myeloma 2011, 11 (Leuk. Suppl 1) S2-S6
8. Knauf, W. U.; Lissitchkov, T.; Aldaoud, A.; Liberati, A. M.; Loscertales, J.; Herbrecht, R.; Juliusson, G.; Postner, G.; Gercheva, L.; Goranov, S.; Becker, M.; Fricke, H. J.; Huguet, F.; Del Giudice, I.; Klein, P.; Merkle, K.; Montillo, M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial Br. J. Hamaetol. 2012, 159, 67-77
9. Chen, L. B. Mitochondrial membrane potential in living cells Annu. Rev. Cell Biol. 1988, 4, 155-181 (Pubitemid 19139255)
10. Cullinane, C.; Bohr, V. A. DNA interstrand cross-links induced by psoralen are not repaired in mammalian mitochondria Cancer Res. 1998, 58, 1400-1404 (Pubitemid 28193599)
11. LeDoux, S. P.; Wilson, G. L.; Beecham, E. J.; Stevnsner, T.; Wassermann, K.; Bohr, V. A. Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells Carcinogenesis 1992, 13, 1967-1973
12. Amrein, L.; Loignon, M.; Goulet, A. C.; Dunn, M.; Jean-Claude, B.; Aloyz, R.; Panasci, L. Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[ h ]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase J. Pharmacol. Exp. Ther. 2007, 321, 848-855 (Pubitemid 46762695)
13. Koczor, C. A.; Shokolenko, I. N.; Boyd, A. K.; Balk, S. P.; Wilson, G. L.; LeDoux, S. P. Mitochondrial DNA damage initiates a cell cycle arrest by a Chk2-associated mechanism in mammalian cells J. Biol. Chem. 2009, 284, 36191-36201
14. Martinez-Diez, M.; Santamaria, G.; Ortega, Å. D.; Cuezva, J. M. Biogenesis and dynamics of mitochondria during the cell cycle: significance of 3′UTRs PLoS One 2006, 1, e107
15. Kuo, L. J.; Yang, L. X. g-H2AX-a novel biomarker for DNA double-strand breaks In Vivo 2008, 22, 305-309
16. Pedersen, P. J.; Christensen, M. S.; Ruysschaert, T.; Linderoth, L.; Andresen, T. L.; Melander, F.; Mouritsen, O. G.; Madsen, R.; Clausen, M. H. Synthesis and biophysical characterization of chlorambucil anticancer ether lipid prodrugs J. Med. Chem. 2009, 52, 3408-3415
17. Myrberg, H.; Zhang, L.; Mae, M.; Langel, U. Design of a tumor-homing cell-penetrating peptide Bioconjugate Chem. 2008, 19, 70-75 (Pubitemid 351213837)
18. Bielawski, K.; Bielawska, A. Small-molecule based delivery systems for alkylating antineoplastic compounds ChemMedChem 2008, 3, 536-542
19. Beyer, U.; Roth, T.; Schumacher, P.; Maier, G.; Unold, A.; Frahm, A. W.; Fiebig, H. H.; Unger, C.; Kratz, F. Synthesis and in vitro efficacy of transferrin conjugates of the anticancer drug chlorambucil J. Med. Chem. 1998, 41, 2701-2708 (Pubitemid 28350337)
20. Stark, P. A.; Thrall, B. D.; Meadows, G. G.; Abdel-Monem, M. M. Synthesis and evaluation of novel spermidine derivatives as targeted cancer chemotherapeutic agents J. Med. Chem. 1992, 35, 4264-4269
21. Descoteaux, C.; Brasseur, K.; Leblanc, V.; Parent, S.; Asselin, E.; Berube, G. Design of novel tyrosine-nitrogen mustard hybrid molecules active against uterine, ovarian and breast cancer cell lines Steroids 2012, 77, 403-412
22. Guaragna, A.; Chiaviello, A.; Paolella, C.; D'Alonzo, D.; Palumbo, G. Synthesis and evaluation of folate-based chlorambucil delivery systems for tumor-targeted chemotherapy Bioconjugate Chem. 2012, 23, 84-96
23. Bielawska, A.; Bielawski, K.; Muszynska, A. Synthesis and biological evaluation of new cyclic amidine analogs of chlorambucil Farmaco 2004, 59, 111-117 (Pubitemid 38198267)
24. Clavel, C. M.; Zava, O.; Schmitt, F.; Kenzaoui, B. H.; Nazarov, A. A.; Juillerat-Jeanneret, L.; Dyson, P. J. Thermoresponsive chlorambucil derivatives for tumour targeting Angew. Chem., Int. Ed. Engl. 2011, 50, 7124-7127
25. Goff, R. D.; Thorson, J. S. Assessment of chemoselective neoglycosylation methods using chlorambucil as a model J. Med. Chem. 2010, 53, 8129-8139
26. Descoteaux, C.; Leblanc, V.; Brasseur, K.; Gupta, A.; Asselin, E.; Berube, G. Synthesis of d-and l -tyrosine-chlorambucil analogs active against breast cancer cell lines Bioorg. Med. Chem. Lett. 2010, 20, 7388-7392
27. Gupta, A.; Saha, P.; Descoteaux, C.; Leblanc, V.; Asselin, E.; Berube, G. Design, synthesis and biological evaluation of estradiol-chlorambucil hybrids as anticancer agents Bioorg. Med. Chem. Lett. 2010, 20, 1614-1618
28. Evers, B.; Schut, E.; van der Burg, E.; Braumuller, T. M.; Egan, D. A.; Holstege, H.; Edser, P.; Adams, D. J.; Wade-Martins, R.; Bouwman, P.; Jonkers, J. A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors Clin. Cancer Res. 2010, 16, 99-108
29. van der Heijden, M. S.; Brody, J. R.; Dezentje, D. A.; Gallmeier, E.; Cunningham, S. C.; Swartz, M. J.; DeMarzo, A. M.; Offerhaus, G. J.; Isacoff, W. H.; Hruban, R. H.; Kern, S. E. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor Clin. Cancer Res. 2005, 11, 7508-7515 (Pubitemid 41507712)
30. Heerdt, B. G.; Houston, M. A.; Augenlicht, L. H. Growth properties of colonic tumor cells are a function of the intrinsic mitochondrial membrane potential Cancer Res. 2006, 66, 1591-1596 (Pubitemid 43259942)
31. Heerdt, B. G.; Houston, M. A.; Augenlicht, L. H. The intrinsic mitochondrial membrane potential of colonic carcinoma cells is linked to the probability of tumor progression Cancer Res. 2005, 65, 9861-9867 (Pubitemid 41541465)
32. Heerdt, B. G.; Houston, M. A.; Wilson, A. J.; Augenlicht, L. H. The intrinsic mitochondrial membrane potential (Δψm) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis Cancer Res. 2003, 63, 6311-6319 (Pubitemid 37255178)
33. Fedeles, B. I.; Zhu, A. Y.; Young, K. S.; Hillier, S. M.; Proffitt, K. D.; Essigmann, J. M.; Croy, R. G. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target J. Biol. Chem. 2011, 286, 33910-33920
34. Hillier, S. M.; Marquis, J. C.; Zayas, B.; Wishnok, J. S.; Liberman, R. G.; Skipper, P. L.; Tannenbaum, S. R.; Essigmann, J. M.; Croy, R. G. DNA adducts formed by a novel antitumor agent 11beta-dichloro in vitro and in vivo Mol. Cancer Ther. 2006, 5, 977-984 (Pubitemid 43724598)
35. Fonseca, S. B.; Pereira, M. P.; Mourtada, R.; Gronda, M.; Horton, K. L.; Hurren, R.; Minden, M. D.; Schimmer, A. D.; Kelley, S. O. Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells Chem. Biol. 2011, 18, 445-453
36. Agapova, L. S.; Chernyak, B. V.; Domnina, L. V.; Dugina, V. B.; Efimenko, A. Y.; Fetisova, E. K.; Ivanova, O. Y.; Kalinina, N. I.; Khromova, N. V.; Kopnin, B. P.; Kopnin, P. B.; Korotetskaya, M. V.; Lichinitser, M. R.; Lukashev, A. L.; Pletjushkina, O. Y.; Popova, E. N.; Skulachev, M. V.; Shagieva, G. S.; Stepanova, E. V.; Titova, E. V.; Tkachuk, V. A.; Vasiliev, J. M.; Skulachev, V. P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells Biochemistry (Moscow) 2008, 73, 1300-1316
37. Ross, M. F.; Da Ros, T.; Blaikie, F. H.; Prime, T. A.; Porteous, C. M.; Severina, I. I.; Skulachev, V. P.; Kjaergaard, H. G.; Smith, R. A.; Murphy, M. P. Accumulation of lipophilic dications by mitochondria and cells Biochem. J. 2006, 400, 199-208 (Pubitemid 44763835)
38. Ross, M. F.; Kelso, G. F.; Blaikie, F. H.; James, A. M.; Cocheme, H. M.; Filipovska, A.; Da Ros, T.; Hurd, T. R.; Smith, R. A.; Murphy, M. P. Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology Biochemistry (Moscow) 2005, 70, 222-230 (Pubitemid 40512331)
39. Liberman, E. A.; Topaly, V. P.; Tsofina, L. M.; Jasaitis, A. A.; Skulachev, V. P. Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria Nature 1969, 222, 1076-1078
40. Murphy, M. P. Targeting lipophilic cations to mitochondria Biochim. Biophys. Acta, Bioenerg. 2008, 1777, 1028-1031
41. Ross, M. F.; Prime, T. A.; Abakumova, I.; James, A. M.; Porteous, C. M.; Smith, R. A.; Murphy, M. P. Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells Biochem. J. 2008, 411, 633-645 (Pubitemid 351600748)
42. Snow, B. J.; Rolfe, F. L.; Lockhart, M. M.; Frampton, C. M.; O'Sullivan, J. D.; Fung, V.; Smith, R. A.; Murphy, M. P.; Taylor, K. M. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease Movement Disord. 2010, 25, 1670-1674
43. Gane, E. J.; Weilert, F.; Orr, D. W.; Keogh, G. F.; Gibson, M.; Lockhart, M. M.; Frampton, C. M.; Taylor, K. M.; Smith, R. A.; Murphy, M. P. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients Liver Int. 2010, 30, 1019-1026
44. Smith, R. A. J.; Murphy, M. P. Animal and human studies with the mitochondria-targeted antioxidant MitoQ Ann. N. Y. Acad. Sci. 2010, 1201, 96-103
45. 64Cu-labeled phosphonium cations as PET radiotracers for tumor imaging Bioconjugate Chem. 2011, 22, 1459-1472
46. Li, Z.; Lopez, M.; Hardy, M.; McAllister, D. M.; Kalyanaraman, B.; Zhao, M. A (99m)Tc-labeled triphenylphosphonium derivative for the early detection of breast tumors Cancer Biother. Radiopharm. 2009, 24, 579-587
47. 64Cu-labeled 2-(diphenylphosphoryl) ethyldiphenylphosphonium cations as highly selective tumor imaging agents: effects of linkers and chelates on radiotracer biodistribution characteristics Bioconjugate Chem. 2008, 19, 2008-2022
48. Wang, J.; Yang, C. T.; Kim, Y. S.; Sreerama, S. G.; Cao, Q.; Li, Z. B.; He, Z.; Chen, X.; Liu, S. 64Cu-Labeled triphenylphosphonium and triphenylarsonium cations as highly tumor-selective imaging agents J. Med. Chem. 2007, 50, 5057-5069 (Pubitemid 47585703)
49. Madar, I.; Weiss, L.; Izbicki, G. Preferential accumulation of (3)H-tetraphenylphosphonium in non-small cell lung carcinoma in mice: comparison with (99m)Tc-MIBI J. Nucl. Med. 2002, 43, 234-238 (Pubitemid 34151048)
50. Millard, M.; Pathania, D.; Shabaik, Y.; Taheri, L.; Deng, J.; Neamati, N. Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity PLoS One 2010, 5, e13131
51. Manetta, A.; Gamboa, G.; Nasseri, A.; Podnos, Y. D.; Emma, D.; Dorion, G.; Rawlings, L.; Carpenter, P. M.; Bustamante, A.; Patel, J.; Rideout, D. Novel phosphonium salts display in vitro and in vivo cytotoxic activity against human ovarian cancer cell lines Gynecol. Oncol. 1996, 60, 203-212 (Pubitemid 26060727)
52. McLean, A.; Newell, D.; Baker, G.; Connors, T. The metabolism of chlorambucil Biochem. Pharmacol. 1980, 29, 2039-2047 (Pubitemid 10077082)
53. Lee, F. Y.; Coe, P.; Workman, P. Pharmacokinetic basis for the comparative antitumour activity and toxicity of chlorambucil, phenylacetic acid mustard and beta, beta-difluorochlorambucil (CB 7103) in mice Cancer Chemother. Pharmacol. 1986, 17, 21-9 (Pubitemid 16113821)
54. Mirkes, P. E.; Greenaway, J. C. Teratogenicity of chlorambucil in rat embryos in vitro Teratology 1982, 26, 135-143 (Pubitemid 13203980)
55. Hidalgo, M. Pancreatic cancer N. Engl. J. Med. 2010, 362, 1605-17
56. Mathews, L. A.; Cabarcas, S. M.; Hurt, E. M.; Zhang, X.; Jaffee, E. M.; Farrar, W. L. Increased expression of DNA repair genes in invasive human pancreatic cancer cells Pancreas 2011, 40, 730-739
57. Mao, Z.; Jiang, Y.; Liu, X.; Seluanov, A.; Gorbunova, V. DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells Neoplasia 2009, 11, 683-691
58. Li, Y.-H.; Wang, X.; Pan, Y.; Lee, D.-H.; Chowdhury, D.; Kimmelman, A. C. Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response PLoS One 2012, 7, e39588
59. Kondo, N.; Takahashi, A.; Ono, K.; Ohnishi, T. DNA damage induced by alkylating agents and repair pathways J. Nucleic Acids 2010, 2010, 543531
60. Shaheen, M.; Allen, C.; Nickoloff, J. A.; Hromas, R. Synthetic lethality: exploiting the addiction of cancer to DNA repair Blood 2011, 117, 6074-6082
61. Mourtada, R.; Fonseca, S. B.; Wisnovsky, S. P.; Pereira, M. P.; Wang, X.; Hurren, R.; Parfitt, J.; Larsen, L.; Smith, R. A.; Murphy, M. P.; Schimmer, A. D.; Kelley, S. O. Redirecting an alkylating agent to mitochondria alters drug target and cell death mechanism PLoS One 2013, 8, e60253
62. Owusu-Ansah, E.; Yavari, A.; Mandal, S.; Banerjee, U. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint Nature Genet. 2008, 40, 356-361 (Pubitemid 351311760)
63. Rehman, J.; Zhang, H. J.; Toth, P. T.; Zhang, Y.; Marsboom, G.; Hong, Z.; Salgia, R.; Husain, A. N.; Wietholt, C.; Archer, S. L. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer FASEB J 2012, 26, 2175-2186
64. Shabaik, Y. H.; Millard, M.; Neamati, N. Mechanistic evaluation of a novel small molecule targeting mitochondria in pancreatic cancer cells PLoS One 2013, 8, e54346
65. Tann, A. W.; Boldogh, I.; Meiss, G.; Qian, W.; Van Houten, B.; Mitra, S.; Szczesny, B. Apoptosis induced by persistent single-strand breaks in the mitochondrial genome: critical role of EXOG (5′EXO/endonuclease) in their repair J. Biol. Chem. 2011, 286, 31975-31983
66. Delsite, R. L.; Rasmussen, L. J.; Rasmussen, A. K.; Kalen, A.; Goswami, P. C.; Singh, K. K. Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus Mutagenesis 2003, 18, 497-503 (Pubitemid 37461550)
67. Hashiguchi, K.; Zhang-Akiyama, Q.-M. Establishment of human cell lines lacking mitochondrial DNA. In Mitochondrial DNA; Stuart, J. A., Ed.; Humana Press: Totowa, NJ, 2009; Vol. 554, pp 383-391.