Small molecule inhibitors of Bcl-2 family proteins for pancreatic cancer therapy

Cancers

Volumn 3, Issue 2, 2011, Pages 1527-1549

  Masood, Ashiq ^a   Azmi, Asfar S ^b   Mohammad, Ramzi M ^a,c  

^a WAYNE STATE UNIVERSITY   (United States)

^b WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c KARMANOS CANCER INSTITUTE   (United States)

Author keywords

Apoptosis; Bcl 2 family proteins; Cancer therapy; PC; Small molecule inhibitors

Indexed keywords

2 AMINO 6 BROMO 4 (1 CYANO 2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLIC ACID ETHYL ESTER; 4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; ABT 269; ANTISENSE OLIGONUCLEOTIDE; APOGOSSYPOLONE; BIM PROTEIN; BL 193; BORTEZOMIB; CISPLATIN; DOCETAXEL; GEMCITABINE; GENISTEIN; GOSSYPOL; GOSSYPOL DERIVATIVE; ISOSORBIDE; JAGGED1; NAVITOCLAX; NOTCH1 RECEPTOR; OBATOCLAX; OBLIMERSEN; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL 2 INHIBITOR; PROTEIN BCL XL; PROTEIN INHIBITOR; PROTEIN MCL 1; PROTEINASE ACTIVATED RECEPTOR 4; RITUXIMAB; TOPOTECAN; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; TW 37; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL CULTURE; CELL CYCLE ARREST; CELL CYCLE S PHASE; CELL SURVIVAL; CHEMOSENSITIZATION; CHRONIC LYMPHATIC LEUKEMIA; DRUG EFFICACY; DRUG POTENCY; DRUG POTENTIATION; DRUG RESEARCH; DRUG TARGETING; FOLLICULAR LYMPHOMA; GLIOMA; HUMAN; INHIBITION KINETICS; LEUKEMIA; LUNG SMALL CELL CANCER; LYMPHOCYTOPENIA; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MANTLE CELL LYMPHOMA; MELANOMA; MOLECULAR INTERACTION; MULTIPLE MYELOMA; NONHUMAN; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; PROTEIN EXPRESSION; RADIOSENSITIVITY; RECEPTOR DOWN REGULATION; REVIEW; SIGNAL TRANSDUCTION; THROMBOCYTOPENIA;

EID: 79959745271     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers3021527     Document Type: Review

References (129)

1. Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 2010, 60, 277-300.
2. Sun, C.Y.; Wang, B.L.; Hu, C.Q.; Peng, R.Y.; Gao, Y.B.; Gu, Q.Y.; Wang, D.W. Expression of the bcl-2 gene and its significance in human pancreatic carcinoma. Hepatobiliary Pancreat. Dis. Int. 2002, 1, 306-308.
3. Ghaneh, P.; Tudur-Smith, C.; Neoptolemos, J.P. Comment on adjuvant therapy in pancreatic cancer: a critical appraisal. Drugs 2007, 67, 2487-2490.
4. Ghaneh, P.; Costello, E.; Neoptolemos, J.P. Biology and management of pancreatic cancer. Postgrad. Med. J. 2008, 84, 478-497.
5. Arlt, A.; Muerkoster, S.S.; Schafer, H. Targeting apoptosis pathways in pancreatic cancer. Cancer Lett. 2010, doi:10.1016/j.canlet.2010.10.015.
6. Maitra, A.; Hruban, R.H. A new mouse model of pancreatic cancer: PTEN gets its Akt together. Cancer Cell 2005, 8, 171-172.
7. Diamantidis, M.; Tsapournas, G.; Kountouras, J.; Zavos, C. New aspects of regulatory signaling pathways and novel therapies in pancreatic cancer. Curr. Mol. Med. 2008, 8, 12-37.
8. Koliopanos, A.; Avgerinos, C.; Paraskeva, C.; Touloumis, Z.; Kelgiorgi, D.; Dervenis, C. Molecular aspects of carcinogenesis in pancreatic cancer. Hepatobiliary Pancreat. Dis. Int. 2008, 7, 345-356.
9. Campani, D.; Esposito, I.; Boggi, U.; Cecchetti, D.; Menicagli, M.; De, N.F.; Colizzi, L.; Del, C.M.; Mosca, F.; Fornaciari, G.; Bevilacqua, G. Bcl-2 expression in pancreas development and pancreatic cancer progression. J. Pathol. 2001, 194, 444-450.
10. Martin, A.P.; Park, M.A.; Mitchell, C.; Walker, T.; Rahmani, M.; Thorburn, A.; Haussinger, D.; Reinehr, R.; Grant, S.; Dent, P. BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing. Mol. Pharmacol. 2009, 76, 327-341.
11. Azmi, A.S.; Wang, Z.; Philip, P.A.; Mohammad, R.M.; Sarkar, F.H. Emerging Bcl-2 inhibitors for the treatment of cancer. Expert Opin. Emerg. Drugs 2010, 16, 59-70
12. Azmi, A.S.; Mohammad, R.M. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J. Cell Physiol. 2009, 218, 13-21.
13. Vo, T.T.; Letai, A. BH3-only proteins and their effects on cancer. Adv. Exp. Med. Biol. 2010, 687, 49-63.
14. Regula, K.M.; Ens, K.; Kirshenbaum, L.A. IKK beta is required for Bcl-2-mediated NF-kappa B activation in ventricular myocytes. J. Biol. Chem. 2002, 277, 38676-38682.
15. Mortenson, M.M.; Galante, J.G.; Gilad, O.; Schlieman, M.G.; Virudachalam, S.; Kung, H.J.; Bold, R.J. BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer. J. Cell Biochem. 2007, 102, 1171-1179.
16. Fahy, B.N.; Schlieman, M.G.; Mortenson, M.M.; Virudachalam, S.; Bold, R.J. Targeting BCL-2 overexpression in various human malignancies through NF-kappaB inhibition by the proteasome inhibitor bortezomib. Cancer Chemother. Pharmacol. 2005, 56, 46-54.
17. Kumar, P.; Ning, Y.; Polverini, P.J. Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion. Lab. Invest. 2008, 88, 740-749.
18. Azmi AS.; Philip P.A.; Zafar SF.; Mohammad RM. PAR-4 as a possible new target for pancreatic cancer therapy. Expert Opin. Ther. Targets 2010, 14, 611-620
19. Tucker, C.A.; Kapanen, A.I.; Chikh, G.; Hoffman, B.G.; Kyle, A.H.; Wilson, I.M.; Masin, D.; Gascoyne, R.D.; Bally, M.; Klasa, R.J. Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-kappaB, p53, bax, and p27 levels. Mol. Cancer Ther. 2008, 7, 749-758.
20. Anai, S.; Shiverick, K.; Medrano, T.; Nakamura, K.; Goodison, S.; Brown, B.D.; Rosser, C.J. Downregulation of BCL-2 induces downregulation of carbonic anhydrase IX, vascular endothelial growth factor, and pAkt and induces radiation sensitization. Urology 2007, 70, 832-837.
21. Crimi, M.; Esposti, M.D. Apoptosis-induced changes in mitochondrial lipids. Biochim. Biophys. Acta 2010, doi: 10.1016/j.bbamcr.2010.09.014.
22. Fulda, S. Exploiting mitochondrial apoptosis for the treatment of cancer. Mitochondrion 2010, 10, 598-603
23. Martinvalet, D.; Zhu, P.; Lieberman, J. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 2005, 22, 355-370.
24. Sprick, M.R.; Walczak, H. The interplay between the Bcl-2 family and death receptor-mediated apoptosis. Biochim. Biophys. Acta 2004, 1644, 125-132.
25. Martinvalet, D.; Zhu, P.; Lieberman, J. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 2005, 22, 355-370.
26. Kumar, R.; Herbert, P.E.; Warrens, A.N. An introduction to death receptors in apoptosis. Int. J. Surg. 2005, 3, 268-277.
27. Hockenbery, D.M. Targeting mitochondria for cancer therapy. Environ. Mol. Mutagen. 2010, 51, 476-489.
28. Czabotar, P.E.; Lessene, G. Bcl-2 family proteins as therapeutic targets. Curr. Pharm. Des. 2010, 16, 3132-3148.
29. Petros, A.M.; Huth, J.R.; Oost, T.; Park, C.M.; Ding, H.; Wang, X.; Zhang, H.; Nimmer, P.; Mendoza, R.; Sun, C.; Mack, J.; Walter, K.; Dorwin, S.; Gramling, E.; Ladror, U.; Rosenberg, S.H.; Elmore, S.W.; Fesik, S.W.; Hajduk, P.J. Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR. Bioorg. Med. Chem. Lett. 2010, 20, 6587-6591.
30. Walensky, L.D. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ. 2006, 13, 1339-1350.
31. Bakhshi, A.; Wright, J.J.; Graninger, W.; Seto, M.; Owens, J.; Cossman, J.; Jensen, J.P.; Goldman, P.; Korsmeyer, S.J. Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners. Proc. Natl. Acad. Sci. USA 1987, 84, 2396-2400.
32. Newmeyer, D.D.; Ferguson-Miller, S. Mitochondria: Releasing power for life and unleashing the machineries of death. Cell 2003, 112, 481-490.
33. Petros, A.M.; Olejniczak, E.T.; Fesik, S.W. Structural biology of the Bcl-2 family of proteins. Biochim. Biophys. Acta 2004, 1644, 83-94.
34. Youle, R.J.; Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008, 9, 47-59.
35. Lomonosova, E.; Chinnadurai, G. BH3-only proteins in apoptosis and beyond: An overview. Oncogene 2008, 27 (Suppl. 1), S2-S19.
36. Richardson, A.; Kaye, S.B. Pharmacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr. Mol. Pharmacol. 2008, 1, 244-254.
37. Giam, M.; Huang, D.C.; Bouillet, P. BH3-only proteins and their roles in programmed cell death. Oncogene 2008, 27 Suppl 1, S128-S136.
38. Borutaite, V. Mitochondria as decision-makers in cell death. Environ. Mol. Mutagen. 2010, 51, 406-416.
39. Tait, S.W.; Green, D.R. Mitochondria and cell death: Outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell. Biol. 2010, 11, 621-632.
40. Cotter, F.E.; Waters, J.; Cunningham, D. Human Bcl-2 antisense therapy for lymphomas. Biochim. Biophys. Acta 1999, 1489, 97-106.
41. Waters, J.S.; Webb, A.; Cunningham, D.; Clarke, P.A.; Raynaud, F.; di, S.F.; Cotter, F.E. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 2000, 18, 1812-1823.
42. Mohammad, R.; Abubakr, Y.; Dan, M.; Aboukameel, A.; Chow, C.; Mohamed, A.; Hamdy, N.; Al-Katib, A. Bcl-2 antisense oligonucleotides are effective against systemic but not central nervous system disease in severe combined immunodeficient mice bearing human t(14;18) follicular lymphoma. Clin. Cancer Res. 2002, 8, 1277-1283.
43. Herbst, R.S.; Frankel, S.R. Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): A rational therapeutic to enhance apoptosis in therapy of lung cancer. Clin. Cancer Res. 2004, 10, 4245s-4248s.
44. Sternberg, C.N.; Dumez, H.; Van, P.H.; Skoneczna, I.; Sella, A.; Daugaard, G.; Gil, T.; Graham, J.; Carpentier, P.; Calabro, F.; Collette, L.; Lacombe, D. Docetaxel plus oblimersen sodium (Bcl- 2 antisense oligonucleotide): An EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer. Ann. Oncol. 2009, 20, 1264-1269.
45. Moulder, S.L.; Symmans, W.F.; Booser, D.J.; Madden, T.L.; Lipsanen, C.; Yuan, L.; Brewster, A.M.; Cristofanilli, M.; Hunt, K.K.; Buchholz, T.A.; Zwiebel, J.; Valero, V.; Hortobagyi, G.N.; Esteva, F.J. Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer. Clin. Cancer Res. 2008, 14, 7909-7916.
46. Rom, J.; von, M.G.; Marme, F.; Ataseven, B.; Kozian, D.; Sievert, M.; Schlehe, B.; Schuetz, F.; Scharf, A.; Kaufmann, M.; Sohn, C.; Schneeweiss, A. Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer. Ann. Oncol. 2009, 20, 1829-1835.
47. Rom, J.; von, M.G.; Eiermann, W.; Sievert, M.; Schlehe, B.; Marme, F.; Schuetz, F.; Scharf, A.; Eichbaum, M.; Sinn, H.P.; Kaufmann, M.; Sohn, C.; Schneeweiss, A. Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study. Ann. Oncol. 2008, 19, 1698-1705.
48. Mita, M.M.; Ochoa, L.; Rowinsky, E.K.; Kuhn, J.; Schwartz, G.; Hammond, L.A.; Patnaik, A.; Yeh, I.T.; Izbicka, E.; Berg, K.; Tolcher, A.W. A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer. Ann. Oncol. 2006, 17, 313-321.
49. Rudin, C.M.; Salgia, R.; Wang, X.; Hodgson, L.D.; Masters, G.A.; Green, M.; Vokes, E.E. Randomized phase II Study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J. Clin. Oncol. 2008, 26, 870-876.
50. Tolcher, A.W.; Chi, K.; Kuhn, J.; Gleave, M.; Patnaik, A.; Takimoto, C.; Schwartz, G.; Thompson, I.; Berg, K.; D'Aloisio, S.; Murray, N.; Frankel, S.R.; Izbicka, E.; Rowinsky, E. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 2005, 11, 3854-3861.
51. Adis International Limited. Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium. Drugs R. D. 2007, 8, 321-334.
52. Xu, Z.; Friess, H.; Solioz, M.; Aebi, S.; Korc, M.; Kleeff, J.; Buchler, M.W. Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine. Int. J. Cancer. 2001, 94, 268-274.
53. Cohen-Saidon, C.; Nechushtan, H.; Kahlon, S.; Livni, N.; Nissim, A.; Razin, E. A novel strategy using single-chain antibody to show the importance of Bcl-2 in mast cell survival. Blood 2003, 102, 2506-2512.
54. Wang, J.L.; Zhang, Z.J.; Choksi, S.; Shan, S.; Lu, Z.; Croce, C.M.; Alnemri, E.S.; Korngold, R.; Huang, Z. Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells. Cancer Res. 2000, 60, 1498-1502.
55. Gleave, M.E.; Monia, B.P. Antisense therapy for cancer. Nat. Rev. Cancer 2005, 5, 468-479.
56. Pitter, K.; Bernal, F.; Labelle, J.; Walensky, L.D. Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008, 446, 387-408.
57. Walensky, L.D.; Pitter, K.; Morash, J.; Oh, K.J.; Barbuto, S.; Fisher, J.; Smith, E.; Verdine, G.L.; Korsmeyer, S.J. A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 2006, 24, 199-210.
58. Walensky, L.D.; Kung, A.L.; Escher, I.; Malia, T.J.; Barbuto, S.; Wright, R.D.; Wagner, G.; Verdine, G.L.; Korsmeyer, S.J. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004, 305, 1466-1470.
59. Bird, G.H.; Bernal, F.; Pitter, K.; Walensky, L.D. Synthesis and biophysical characterization of stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008, 446, 369-386.
60. Brajuskovic, G.; Orolicki, S.V.; Cerovic, S.; Usaj, S.K.; Marjanovic, S.; Romac, S. Bcl-2 and Bax protein interaction in B-lymphocytes of peripheral blood in patients with chronic lymphocytic leukemia. Vojnosanit. Pregl. 2005, 62, 357-363.
61. Raisova, M.; Hossini, A.M.; Eberle, J.; Riebeling, C.; Wieder, T.; Sturm, I.; Daniel, P.T.; Orfanos, C.E.; Geilen, C.C. The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J. Invest. Dermatol. 2001, 117, 333-340.
62. Van, D., V; Wever, P.C.; Van Diepen, F.N.; Yong, S.L.; Ten, B., I. Quantification of Bax/Bcl-2 ratios in peripheral blood lymphocytes, monocytes and granulocytes and their relation to susceptibility to anti-Fas (anti-CD95)-induced apoptosis. Clin. Exp. Immunol. 1997, 110, 324-328.
63. Korsmeyer, S.J.; Shutter, J.R.; Veis, D.J.; Merry, D.E.; Oltvai, Z.N. Bcl-2/Bax: A rheostat that regulates an anti-oxidant pathway and cell death. Semin. Cancer. Biol. 1993, 4, 327-332.
64. Muchmore, S.W.; Sattler, M.; Liang, H.; Meadows, R.P.; Harlan, J.E.; Yoon, H.S.; Nettesheim, D.; Chang, B.S.; Thompson, C.B.; Wong, S.L.; Ng, S.L.; Fesik, S.W. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996, 381, 335-341.
65. Withers, W.A.; Carruth, F.E. Gossypol- A toxic substance in cottonseed. A prelimnary note. Science 1915, 41, 324.
66. Ohuchi, K.; Watanabe, M.; Hirasawa, N.; Tsurufuji, S.; Ozeki, T.; Fujiki, H. Inhibition by gossypol of tumor promoter-induced arachidonic acid metabolism in rat peritoneal macrophages. Biochim. Biophys. Acta 1988, 971, 85-91.
67. Liu, G.Z.; Lyle, K.C.; Cao, J. Clinical trial of gossypol as a male contraceptive drug. Part I. Efficacy study. Fertil. Steril. 1987, 48, 459-461.
68. Hu, F.; Mah, K.; Teramura, D.J. Gossypol effects on cultured normal and malignant melanocytes. In vitro Cell Dev. Biol. 1986, 22, 583-588.
69. Li XX.; Ge RS.; Zhang YG.; Shi QX.; Spermicidal effects in vitro of gossypol acetic acidpovidone coprecipitate. Zhongguo Yao Li Xue Bao 1986, 7, 453-456.
70. Wang, X.; Howell, C.P.; Chen, F.; Yin, J.; Jiang, Y. Gossypol-A polyphenolic compound from cotton plant. Adv. Food Nutr. Res. 2009, 58, 215-263.
71. Kang, M.H.; Reynolds, C.P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 2009, 15, 1126-1132.
72. Bushunow, P.; Reidenberg, M.M.; Wasenko, J.; Winfield, J.; Lorenzo, B.; Lemke, S.; Himpler, B.; Corona, R.; Coyle, T. Gossypol treatment of recurrent adult malignant gliomas. J. Neurooncol. 1999, 43, 79-86.
73. Wang, G.; Nikolovska-Coleska, Z.; Yang, C.Y.; Wang, R.; Tang, G.; Guo, J.; Shangary, S.; Qiu, S.; Gao, W.; Yang, D.; Meagher, J.; Stuckey, J.; Krajewski, K.; Jiang, S.; Roller, P.P.; Abaan, H.O.; Tomita Y.; Wang, S. Structure-based design of potent small-molecule inhibitors of antiapoptotic Bcl-2 proteins. J. Med. Chem. 2006, 49, 6139-6142.
74. Huang, Y.W.; Wang, L.S.; Chang, H.L.; Ye, W.; Dowd, M.K.; Wan, P.J.; Lin, Y.C. Molecular mechanisms of (-)-gossypol-induced apoptosis in human prostate cancer cells. Anticancer Res. 2006, 26, 1925-1933.
75. Zaidi, R.; Hadi, S.M. Interaction of gossypol with DNA. Toxicol. In Vitro 1992, 6, 71-76.
76. Zaidi, R.; Hadi, S.M. Strand scission in DNA by gossypol and Cu(II): Role of Cu(I) and oxygenfree radicals. J. Biochem. Toxicol. 1992, 7, 213-217.
77. Volate, S.R.; Kawasaki, B.T.; Hurt, E.M.; Milner, J.A.; Kim, Y.S.; White, J.; Farrar, W.L. Gossypol induces apoptosis by activating p53 in prostate cancer cells and prostate tumorinitiating cells. Mol. Cancer Ther. 2010, 9, 461-470.
78. Voss, V.; Senft, C.; Lang, V.; Ronellenfitsch, M.W.; Steinbach, J.P.; Seifert, V.; Kogel, D. The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol. Cancer. Res. 2010, 8, 1002-1016.
79. Sung, B.; Ravindran, J.; Prasad, S.; Pandey, M.K.; Aggarwal, B.B. Gossypol induces death receptor-5 through activation of ROS-ERK-chop pathway and sensitizes colon cancer cells to trail. J. Biol Chem. 2010, 285, 35418-35427.
80. Mohammad, R.M.; Wang, S.; Aboukameel, A.; Chen, B.; Wu, X.; Chen, J.; Al-Katib, A. Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol. Cancer Ther. 2005, 4, 13-21.
81. Wang, Z.; Song, W.; Aboukameel, A.; Mohammad, M.; Wang, G.; Banerjee, S.; Kong, D.; Wang, S.; Sarkar, F.H.; Mohammad, R.M. TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer. Int J. Cancer. 2008, 123, 958-966.
82. Mohammad, R.M.; Goustin, A.S.; Aboukameel, A.; Chen, B.; Banerjee, S.; Wang, G.; Nikolovska-Coleska, Z.; Wang, S.; Al-Katib, A. Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin. Cancer Res. 2007, 13, 2226-2235.
83. Al-Katib, A.M.; Sun, Y.; Goustin, A.S.; Azmi, A.S.; Chen, B.; Aboukameel, A.; Mohammad, R.M. SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status. J. Hematol. Oncol. 2009, 2, 8.
84. Azmi, A.S.; Wang, Z.; Burikhanov, R.; Rangnekar, V.M.; Wang, G.; Chen, J.; Wang, S.; Sarkar, F.H.; Mohammad, R.M. Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis. Mol. Cancer Ther. 2008, 7, 2884-2893.
85. Zeitlin, B.D.; Joo, E.; Dong, Z.; Warner, K.; Wang, G.; Nikolovska-Coleska, Z.; Wang, S.; Nor, J.E. Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res. 2006, 66, 8698-8706.
86. Mohammad, R.M.; Goustin, A.S.; Aboukameel, A.; Chen, B.; Banerjee, S.; Wang, G.; Nikolovska-Coleska, Z.; Wang, S.; Al-Katib, A. Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin. Cancer Res. 2007, 13, 2226-2235.
87. Wang, Z.; Azmi, A.S.; Ahmad, A.; Banerjee, S.; Wang, S.; Sarkar, F.H.; Mohammad, R.M. TW- 37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway. Cancer Res. 2009, 69, 2757-2765.
88. Sun, Y.; Wu, J.; Aboukameel, A.; Banerjee, S.; Arnold, A.A.; Chen, J.; Nikolovska-Coleska, Z.; Lin, Y.; Ling, X.; Yang, D.; Wang, S.; Al-Katib, A.; Mohammad, R.M. Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. Cancer Biol. Ther. 2008, 7, 1418-1426.
89. Zhang, X.Q.; Huang, X.F.; Hu, X.B.; Zhan, Y.H.; An, Q.X.; Yang, S.M.; Xia, A.J.; Yi, J.; Chen, R.; Mu, S.J.; Wu, D.C. Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro. Asian J. Androl. 2010, 12, 697-708.
90. Banerjee, S.; Choi, M.; Aboukameel, A.; Wang, Z.; Mohammad, M.; Chen, J.; Yang, D.; Sarkar, F.H.; Mohammad, R.M. Preclinical studies of apogossypolone, a novel pan inhibitor of bcl-2 and mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells. Pancreas 2010, 39, 323-331.
91. Sun, J.; Li, Z.M.; Hu, Z.Y.; Zeng, Z.L.; Yang, D.J.; Jiang, W.Q. Apogossypolone inhibits cell growth by inducing cell cycle arrest in U937 cells. Oncol. Rep. 2009, 22, 193-198.
92. Lin, J.; Wu, Y.J.; Yang, D.J.; Zhao, Y.Q. Effect of apogossypolone on induction apoptosis in multiple myeloma cells and its mechanisms. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2009, 17, 92-98.
93. Arnold, A.A.; Aboukameel, A.; Chen, J.; Yang, D.; Wang, S.; Al-Katib, A.; Mohammad, R.M. Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model. Mol. Cancer. 2008, 7, 20.
94. Heist, R.S.; Fain, J.; Chinnasami, B.; Khan, W.; Molina, J.R.; Sequist, L.V.; Temel, J.S.; Fidias, P.; Brainerd, V.; Leopold, L.; Lynch, T.J. Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J. Thorac. Oncol. 2010, 5, 1637-1643.
95. Heist, R.S.; Fain, J.; Chinnasami, B.; Khan, W.; Molina, J.R.; Sequist, L.V.; Temel, J.S.; Fidias, P.; Brainerd, V.; Leopold, L.; Lynch, T.J. Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J. Thorac. Oncol. 2010, 5, 1637-1643.
96. Kang, M.H.; Reynolds, C.P. Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 2009, 15, 1126-1132.
97. Kline, M.P.; Rajkumar, S.V.; Timm, M.M.; Kimlinger, T.K.; Haug, J.L.; Lust, J.A.; Greipp, P.R.; Kumar, S. R-(-)-gossypol (AT-101) activates programmed cell death in multiple myeloma cells. Exp. Hematol. 2008, 36, 568-576.
98. Kline, M.P.; Rajkumar, S.V.; Timm, M.M.; Kimlinger, T.K.; Haug, J.L.; Lust, J.A.; Greipp, P.R.; Kumar, S. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia 2007, 21, 1549-1560.
99. Oltersdorf, T.; Elmore, S.W.; Shoemaker, A.R.; Armstrong, R.C.; Augeri, D.J.; Belli, B.A.; Bruncko, M.; Deckwerth, T.L.; Dinges, J.; Hajduk, P.J.; Joseph, M.K.; Kitada, S.; Korsmeyer, S.J.; Kunzer, A.R.; Letai, A.; Li, C.; Mitten, M.J.; Nettesheim, D.G.; Ng, S.; Nimmer, P.M.; O'Connor, J.M.; Oleksijew, A.; Petros, A.M.; Reed, J.C.; Shen, W.; Tahir, S.K.; Thompson, C.B.; Tomaselli, K.J.; Wang, B.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005, 435, 677-681.
100. Shore, G.C.; Viallet, J. Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. Hematology Am. Soc. Hematol. Educ. Program. 2005, 226-230.
101. Bhat, U.G.; Pandit, B.; Gartel, A.L. ARC synergizes with ABT-737 to induce apoptosis in human cancer cells. Mol. Cancer Ther. 2010, 9, 1688-1696.
102. Olberding, K.E.; Wang, X.; Zhu, Y.; Pan, J.; Rai, S.N.; Li, C. Actinomycin D synergistically enhances the efficacy of the BH3 mimetic: ABT-737 by downregulating Mcl-1 expression. Cancer Biol. Ther. 2010, 10,918-29.
103. Krystal, G.W. Teaching an old drug new tricks: Actinomycin D synergistically enhances sensitivity to the Bcl-2 antagonist ABT-737. Cancer Biol. Ther. 2010, 10, 10, 930-932
104. Xu, H.; Krystal, G.W. Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Clin. Cancer Res. 2010, 16, 4392-4400.
105. Hikita, H.; Takehara, T.; Shimizu, S.; Kodama, T.; Shigekawa, M.; Iwase, K.; Hosui, A.; Miyagi, T.; Tatsumi, T.; Ishida, H.; Li, W.; Kanto, T.; Hiramatsu, N.; Hayashi, N. The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 2010, 52, 1310-1321.
106. Yecies, D.; Carlson, N.E.; Deng, J.; Letai, A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010, 115, 3304-3313.
107. Ackler, S.; Xiao, Y.; Mitten, M.J.; Foster, K.; Oleksijew, A.; Refici, M.; Schlessinger, S.; Wang, B.; Chemburkar, S.R.; Bauch, J.; Tse, C.; Frost, D.J.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W.; Shoemaker, A.R. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol. Cancer Ther. 2008, 7, 3265-3274.
108. Tse, C.; Shoemaker, A.R.; Adickes, J.; Anderson, M.G.; Chen, J.; Jin, S.; Johnson, E.F.; Marsh, K.C.; Mitten, M.J.; Nimmer, P.; Roberts, L.; Tahir, S.K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S.H.; Elmore, S.W. ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008, 68, 3421-3428.
109. Tahir, S.K.; Wass, J.; Joseph, M.K.; Devanarayan, V.; Hessler, P.; Zhang, H.; Elmore, S.W.; Kroeger, P.E.; Tse, C.; Rosenberg, S.H.; Anderson, M.G. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Mol. Cancer Ther. 2010, 9, 545-557.
110. Ackler, S.; Mitten, M.J.; Foster, K.; Oleksijew, A.; Refici, M.; Tahir, S.K.; Xiao, Y.; Tse, C.; Frost, D.J.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W.; Shoemaker, A.R. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother. Pharmacol. 2010, 66, 869-880.
111. Hallek, M.; Pflug, N. Chronic lymphocytic leukemia. Ann Oncol. 2010, 21 (Suppl 7), vii154- vii164.
112. Petros, A.M.; Huth, J.R.; Oost, T.; Park, C.M.; Ding, H.; Wang, X.; Zhang, H.; Nimmer, P.; Mendoza, R.; Sun, C.; Mack, J.; Walter, K.; Dorwin, S.; Gramling, E.; Ladror, U.; Rosenberg, S.H.; Elmore, S.W.; Fesik, S.W.; Hajduk, P.J. Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR. Bioorg. Med. Chem. Lett. 2010, 20, 6587-6591.
113. Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 2010, 9, 447-464.
114. Nguyen, M.; Marcellus, R.C.; Roulston, A.; Watson, M.; Serfass, L.; Murthy, M., Sr.; Goulet, D.; Viallet, J.; Belec, L.; Billot, X.; Acoca, S.; Purisima, E.; Wiegmans, A.; Cluse, L.; Johnstone, R.W.; Beauparlant, P.; Shore, G.C. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc. Natl. Acad. Sci. USA 2007, 104, 19512-19517.
115. Simon, G.; Sharma, A.; Li, X.; Hazelton, T.; Walsh, F.; Williams, C.; Chiappori, A.; Haura, E.; Tanvetyanon, T.; Antonia, S.; Cantor, A.; Bepler, G. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 2007, 25, 2741-2746.
116. Trudel, S.; Li, Z.H.; Rauw, J.; Tiedemann, R.E.; Wen, X.Y.; Stewart, A.K. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood 2007, 109, 5430-5438.
117. Smoot, R.L.; Blechacz, B.R.; Werneburg, N.W.; Bronk, S.F.; Sinicrope, F.A.; Sirica, A.E.; Gores, G.J. A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells. Cancer Res. 2010, 70, 1960-1969.
118. Perez-Galan, P.; Roue, G.; Villamor, N.; Montserrat, E.; Campo, E.; Colomer, D. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 2006, 107, 257-264.
119. Pan, J.; Cheng, C.; Verstovsek, S.; Chen, Q.; Jin, Y.; Cao, Q. The BH3-mimetic GX15-070 induces autophagy, potentiates the cytotoxicity of carboplatin and 5-fluorouracil in esophageal carcinoma cells. Cancer Lett. 2010, 293, 167-174.
120. Huang, S.; Okumura, K.; Sinicrope, F.A. BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 2009, 15, 150-159.
121. Jiang, C.C.; Wroblewski, D.; Yang, F.; Hersey, P.; Zhang, X.D. Human melanoma cells under endoplasmic reticulum stress are more susceptible to apoptosis induced by the BH3 mimetic obatoclax. Neoplasia 2009, 11, 945-955.
122. Wang, J.L.; Liu, D.; Zhang, Z.J.; Shan, S.; Han, X.; Srinivasula, S.M.; Croce, C.M.; Alnemri, E.S.; Huang, Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl. Acad. Sci. USA 2000, 97, 7124-7129.
123. Witters, L.M.; Witkoski, A.; Planas-Silva, M.D.; Berger, M.; Viallet, J.; Lipton, A. Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor. Oncol. Rep. 2007, 17, 465-469.
124. Campas, C.; Cosialls, A.M.; Barragan, M.; Iglesias-Serret, D.; Santidrian, A.F.; Coll-Mulet, L.; de, F.M.; Domingo, A.; Pons, G.; Gil, J. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp. Hematol. 2006, 34, 1663-1669.
125. Skommer, J.; Wlodkowic, D.; Matto, M.; Eray, M.; Pelkonen, J. HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells. Leuk. Res. 2006, 30, 322-331.
126. Doshi, J.M.; Tian, D.; Xing, C. Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)- Hchromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against antiapoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species that induce apoptosis. Mol. Pharm. 2007, 4, 919-928.
127. Konopleva, M.; Watt, J.; Contractor, R.; Tsao, T.; Harris, D.; Estrov, Z.; Bornmann, W.; Kantarjian, H.; Viallet, J.; Samudio, I.; Andreeff, M. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 2008, 68, 3413-3420.
128. Dai, Y.; Grant, S. Targeting multiple arms of the apoptotic regulatory machinery. Cancer Res. 2007, 67, 2908-2911.
129. Mason, K.D.; Carpinelli, M.R.; Fletcher, J.I.; Collinge, J.E.; Hilton, A.A.; Ellis, S.; Kelly, P.N.; Ekert, P.G.; Metcalf, D.; Roberts, A.W.; Huang, D.C.; Kile, B.T. Programmed anuclear cell death delimits platelet life span. Cell 2007, 128, 1173-1186.