Activation of the Proapoptotic Bcl-2 Protein Bax by a Small Molecule Induces Tumor Cell Apoptosis

REFERENCES

• Evan GI, Vousden KH. 2001. Proliferation, cell cycle and apoptosis in cancer. Nature 411:342–348. http://dx.doi.org/10.1038/35077213.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–674. http://dx.doi.org/10.1016/j.cell.2011.02.013.
   PubMed Web of Science ®Google Scholar
• Yip KW, Reed JC. 2008. Bcl-2 family proteins and cancer. Oncogene 27:6398–6406. http://dx.doi.org/10.1038/onc.2008.307.
   PubMed Web of Science ®Google Scholar
• Adams JM, Cory S. 2007. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr. Opin. Immunol. 19:488–496. http://dx.doi.org/10.1016/j.coi.2007.05.004.
   PubMed Web of Science ®Google Scholar
• Hardwick JM, Youle RJ. 2009. SnapShot: BCL-2 proteins. Cell 138:404, 404.e1. http://dx.doi.org/10.1016/j.cell.2009.07.003.
   PubMedGoogle Scholar
• Youle RJ, Strasser A. 2008. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9:47–59. http://dx.doi.org/10.1038/nrm2308.
   PubMed Web of Science ®Google Scholar
• Chipuk JE, Green DR. 2008. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 18:157–164. http://dx.doi.org/10.1016/j.tcb.2008.01.007.
   PubMed Web of Science ®Google Scholar
• Danial NN, Korsmeyer SJ. 2004. Cell death: critical control points. Cell 116:205–219. http://dx.doi.org/10.1016/S0092-8674(04)00046-7.
   PubMed Web of Science ®Google Scholar
• Bose P, Klimowicz AC, Kornaga E, Petrillo SK, Matthews TW, Chandarana S, Magliocco AM, Brockton NT, Dort JC. 2012. Bax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma. BMC Cancer 12:332. http://dx.doi.org/10.1186/1471-2407-12-332.
   PubMedGoogle Scholar
• Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le QJ, Baglietto L, Severi G, Giles GG, McLean CA, Callagy G, Green AR, Ellis I, Gelmon K, Turashvili G, Leung S, Aparicio S, Huntsman D, Caldas C, Pharoah P. 2010. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br. J. Cancer 103:668–675. http://dx.doi.org/10.1038/sj.bjc.6605736.
   PubMed Web of Science ®Google Scholar
• Grange F, Petrella T, Beylot-Barry M, Joly P, d'Incan M, Delaunay M, Machet L, Avril MF, Dalac S, Bernard P, Carlotti A, Esteve E, Vergier B, Dechelotte P, Cassagnau E, Courville P, Saiag P, Laroche L, Bagot M, Wechsler J. 2004. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood 103:3662–3668. http://dx.doi.org/10.1182/blood-2003-08-2726.
   PubMed Web of Science ®Google Scholar
• Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore VG, Deng J, Anderson KC, Richardson P, Tai YT, Mitsiades CS, Matulonis UA, Drapkin R, Stone R, Deangelo DJ, McConkey DJ, Sallan SE, Silverman L, Hirsch MS, Carrasco DR, Letai A. 2011. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334:1129–1133. http://dx.doi.org/10.1126/science.1206727.
   PubMed Web of Science ®Google Scholar
• Ryan JA, Brunelle JK, Letai A. 2010. Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc. Natl. Acad. Sci. U. S. A. 107:12895–12900. http://dx.doi.org/10.1073/pnas.0914878107.
   PubMed Web of Science ®Google Scholar
• Kelly PN, Strasser A. 2011. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. http://dx.doi.org/10.1038/cdd.2011.17.
   PubMed Web of Science ®Google Scholar
• Fesik SW. 2005. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer 5:876–885. http://dx.doi.org/10.1038/nrc1736.
   PubMed Web of Science ®Google Scholar
• Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. 2006. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365. http://dx.doi.org/10.1016/j.ccr.2006.03.027.
   PubMed Web of Science ®Google Scholar
• Vogler M, Dinsdale D, Dyer MJ, Cohen GM. 2009. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ. 16:360–367. http://dx.doi.org/10.1038/cdd.2008.137.
   PubMed Web of Science ®Google Scholar
• Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC. 2007. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc. Natl. Acad. Sci. U. S. A. 104:19512–19517. http://dx.doi.org/10.1073/pnas.0709443104.
   PubMed Web of Science ®Google Scholar
• Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681. http://dx.doi.org/10.1038/nature03579.
   PubMed Web of Science ®Google Scholar
• Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S. 2006. Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J. Med. Chem. 49:6139–6142. http://dx.doi.org/10.1021/jm060460o.
   PubMed Web of Science ®Google Scholar
• Stewart ML, Fire E, Keating AE, Walensky LD. 2010. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat. Chem. Biol. 6:595–601. http://dx.doi.org/10.1038/nchembio.391.
   PubMed Web of Science ®Google Scholar
• Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB. 2000. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol. Cell 6:1389–1399. http://dx.doi.org/10.1016/S1097-2765(00)00136-2.
   PubMed Web of Science ®Google Scholar
• Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. 2001. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. http://dx.doi.org/10.1126/science.1059108.
   PubMed Web of Science ®Google Scholar
• Walensky LD, Gavathiotis E. 2011. BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem. Sci. 36:642–652. http://dx.doi.org/10.1016/j.tibs.2011.08.009.
   PubMed Web of Science ®Google Scholar
• Suzuki M, Youle RJ, Tjandra N. 2000. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103:645–654. http://dx.doi.org/10.1016/S0092-8674(00)00167-7.
   PubMed Web of Science ®Google Scholar
• Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. 2006. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat. Cell Biol. 8:1348–1358. http://dx.doi.org/10.1038/ncb1499.
   PubMed Web of Science ®Google Scholar
• Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. 2002. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342. http://dx.doi.org/10.1016/S0092-8674(02)01036-X.
   PubMed Web of Science ®Google Scholar
• Letai A. 2009. Puma strikes Bax. J. Cell Biol. 185:189–191. http://dx.doi.org/10.1083/jcb.200903134.
   PubMedGoogle Scholar
• Dewson G, Ma S, Frederick P, Hockings C, Tan I, Kratina T, Kluck RM. 2012. Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ. 19:661–670. http://dx.doi.org/10.1038/cdd.2011.138.
   PubMed Web of Science ®Google Scholar
• Bleicken S, Classen M, Padmavathi PV, Ishikawa T, Zeth K, Steinhoff HJ, Bordignon E. 2010. Molecular details of Bax activation, oligomerization, and membrane insertion. J. Biol. Chem. 285:6636–6647. http://dx.doi.org/10.1074/jbc.M109.081539.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Zhu W, Lapolla SM, Miao Y, Shao Y, Falcone M, Boreham D, McFarlane N, Ding J, Johnson AE, Zhang XC, Andrews DW, Lin J. 2010. Bax forms an oligomer via separate, yet interdependent, surfaces. J. Biol. Chem. 285:17614–17627. http://dx.doi.org/10.1074/jbc.M110.113456.
   PubMed Web of Science ®Google Scholar
• Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. 2013. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152:519–531. http://dx.doi.org/10.1016/j.cell.2012.12.031.
   PubMed Web of Science ®Google Scholar
• Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. 2008. BAX activation is initiated at a novel interaction site. Nature 455:1076–1081. http://dx.doi.org/10.1038/nature07396.
   PubMed Web of Science ®Google Scholar
• White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB, Foskett JK. 2005. The endoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat. Cell Biol. 7:1021–1028. http://dx.doi.org/10.1038/ncb1302.
   PubMedGoogle Scholar
• Olberding KE, Wang X, Zhu Y, Pan J, Rai SN, Li C. 2010. Actinomycin D synergistically enhances the efficacy of the BH3 mimetic ABT-737 by downregulating Mcl-1 expression. Cancer Biol. Ther. 10:918–929. http://dx.doi.org/10.4161/cbt.10.9.13274.
   PubMed Web of Science ®Google Scholar
• Wang X, Olberding KE, White C, Li C. 2011. Bcl-2 proteins regulate ER membrane permeability to luminal proteins during ER stress-induced apoptosis. Cell Death Differ. 18:38–47. http://dx.doi.org/10.1038/cdd.2010.68.
   PubMed Web of Science ®Google Scholar
• Pozzan A. 2006. Molecular descriptors and methods for ligand based virtual high throughput screening in drug discovery. Curr. Pharm. Des. 12:2099–2110. http://dx.doi.org/10.2174/138161206777585247.
   PubMed Web of Science ®Google Scholar
• Niesen FH, Berglund H, Vedadi M. 2007. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2:2212–2221. http://dx.doi.org/10.1038/nprot.2007.321.
   PubMed Web of Science ®Google Scholar
• Soejima K, Fang W, Rollins BJ. 2003. DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. Oncogene 22:4723–4733. http://dx.doi.org/10.1038/sj.onc.1206510.
   PubMedGoogle Scholar
• Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B. 2000. Role of BAX in the apoptotic response to anticancer agents. Science 290:989–992. http://dx.doi.org/10.1126/science.290.5493.989.
   PubMed Web of Science ®Google Scholar
• Wang C, Youle RJ. 2012. Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak. Oncogene 31:3177–3189. http://dx.doi.org/10.1038/onc.2011.497.
   PubMed Web of Science ®Google Scholar
• Azzoli CG, Kris MG, Pfister DG. 2007. Cisplatin versus carboplatin for patients with metastatic non-small-cell lung cancer—an old rivalry renewed. J. Natl. Cancer Inst. 99:828–829. http://dx.doi.org/10.1093/jnci/djk222.
   PubMedGoogle Scholar
• Xiros N, Papacostas P, Economopoulos T, Samelis G, Efstathiou E, Kastritis E, Kalofonos H, Onyenadum A, Skarlos D, Bamias A, Gogas H, Bafaloukos D, Samantas E, Kosmidis P. 2005. Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group. Ann. Oncol. 16:773–779. http://dx.doi.org/10.1093/annonc/mdi160.
   PubMed Web of Science ®Google Scholar
• Chou TC. 2010. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. http://dx.doi.org/10.1158/0008-5472.CAN-09-1947.
   PubMed Web of Science ®Google Scholar
• Wells JA, McClendon CL. 2007. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009. http://dx.doi.org/10.1038/nature06526.
   PubMed Web of Science ®Google Scholar
• Lambert JM, Gorzov P, Veprintsev DB, Soderqvist M, Segerback D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ. 2009. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15:376–388. http://dx.doi.org/10.1016/j.ccr.2009.03.003.
   PubMed Web of Science ®Google Scholar
• Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD. 2012. Direct and selective small-molecule activation of proapoptotic BAX. Nat. Chem. Biol. 8:639–645. http://dx.doi.org/10.1038/nchembio.995.
   PubMed Web of Science ®Google Scholar
• Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B, Andrews DW. 2008. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135:1074–1084. http://dx.doi.org/10.1016/j.cell.2008.11.010.
   PubMed Web of Science ®Google Scholar
• Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. 2009. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol. Cell 36:487–499. http://dx.doi.org/10.1016/j.molcel.2009.09.030.
   PubMed Web of Science ®Google Scholar
• Kaelin WGJr. 2005. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5:689–698. http://dx.doi.org/10.1038/nrc1691.
   PubMed Web of Science ®Google Scholar
• Keith CT, Borisy AA, Stockwell BR. 2005. Multicomponent therapeutics for networked systems. Nat. Rev. Drug Discov. 4:71–78. http://dx.doi.org/10.1038/nrd1609.
   PubMed Web of Science ®Google Scholar
• Letai A. 2005. BCL-2: found bound and drugged! Trends Mol. Med. 11:442–444. http://dx.doi.org/10.1016/j.molmed.2005.08.007.
   PubMed Web of Science ®Google Scholar