Abstract
S1 is a putative BH3 mimetic proposed to inhibit BCL2 and MCL1 based on cell-free assays. However, we previously demonstrated that it failed to inhibit BCL2 or induce apoptosis in chronic lymphocytic leukemia (CLL) cells, which are dependent on BCL2 for survival. In contrast, we show here that S1 rapidly increases reactive oxygen species, initiates endoplasmic reticulum stress, and upregulates the BH3-only protein NOXA. The BCL2 inhibitors, ABT-737, ABT-263, and ABT-199, have demonstrated pro-apoptotic efficacy in cell lines, while ABT-263 and ABT-199 have demonstrated efficacy in early clinical trials. Resistance to these inhibitors arises from the upregulation of anti-apoptotic factors, such as MCL1, BFL1, and BCLXL. This resistance can be induced by co-culturing CLL cells on a stromal cell line that mimics the microenvironment found in patients. Since NOXA can inhibit MCL1, BFL1, and BCLXL, we hypothesized that S1 may overcome resistance to ABT-737. Here we demonstrate that S1 induces NOXA-dependent sensitization to ABT-737 in a human promyelocytic leukemia cell line (NB4). Furthermore, S1 sensitized CLL cells to ABT-737 ex vivo, and overcame resistance to ABT-737 induced by co-culturing CLL cells with stroma.
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References
Hanahan D, Weinberg Robert A (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Dewson G, Kluck RM (2009) Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci 122:2801–2808
Walensky LD (2006) BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ 13:1339–1350
Lomonosova E, Chinnadurai G (2008) BH3-only proteins in apoptosis and beyond: an overview. Oncogene 27:S2–S19
Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DCS, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of Navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30:488–496
Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu Y-L, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29:909–916
Yecies D, Carlson NE, Deng J, Letai A (2010) Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 115:3304–3313
Albershardt TC, Salerni BL, Soderquist RS, Bates DJP, Pletnev AA, Kisselev AF, Eastman A (2011) Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 286:24882–24895
van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399
Zhang Z, Jin L, Qian X, Wei M, Wang Y, Wang J, Yang Y, Xu Q, Xu Y, Liu F (2007) Novel Bcl-2 inhibitors: discovery and mechanism study of small organic apoptosis-inducing agents. Chem Bio Chem 8:113–121
Song T, Chang X, Zhang Z, Liu Y, Shen X (2012) S1, a novel pan-BH3 mimetic, induces apoptosis in Mcl-1-overexpressing cells through Bak. J Pharmacol Sci 119:330–340
Salerni BL, Bates DJ, Albershardt TC, Lowrey CH, Eastman A (2010) Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed. Mol Cancer Ther 9:791–802
Bates DJP, Salerni BL, Lowrey CH, Eastman A (2011) Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis. Cancer Biol Ther 12:314–325
Neron S, Pelletier A, Chevrier M-C, Monier G, Lemieux R, Darveau A (1996) Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. Immunol Invest 25:79–89
Lee EF, Czabotar PE, van Delft MF, Michalak EM, Boyle MJ, Willis SN, Puthalakath H, Bouillet P, Colman PM, Huang DCS, Fairlie WD (2008) A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol 180:341–355
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891
Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci 106:2200–2205
Ding W, Yang L, Zhang M, Gu Y (2012) Reactive oxygen species-mediated endoplasmic reticulum stress contributes to aldosterone-induced apoptosis in tubular epithelial cells. Biochem Biophys Res Commun 418:451–456
Zafarullah M, Li WQ, Sylvester J, Ahmad M (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6–20
Mason KD, Khaw SL, Rayeroux KC, Chew E, Lee EF, Fairlie WD, Grigg AP, Seymour JF, Szer J, Huang DCS, Roberts AW (2009) The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 23:2034–2041
Vogler M, Butterworth M, Majid A, Walewska RJ, Sun X-M, Dyer MJS, Cohen GM (2009) Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 113:4403–4413
Vogler M, Weber K, Dinsdale D, Schmitz I, Schulze-Osthoff K, Dyer MJS, Cohen GM (2009) Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ 16:1030–1039
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
Doi K, Li R, Sung S–S, Wu H, Liu Y, Manieri W, Krishnegowda G, Awwad A, Dewey A, Liu X, Amin S, Cheng C, Qin Y, Schonbrunn E, Daughdrill G, Loughran TP, Sebti S, Wang H-G (2012) Discovery of Marinopyrrole A (Maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem 287:10224–10235
Tromp JM, Geest CR, Breij ECW, Elias JA, van Laar J, Luijks DM, Kater AP, Beaumont T, van Oers MHJ, Eldering E (2012) Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia. Clin Cancer Res 18:487–498
Lucas KM, Mohana-Kumaran N, Lau D, Zhang XD, Hersey P, Huang DC, Weninger W, Haass NK, Allen JD (2012) Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737. Clin Cancer Res 18:783–795
Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11:85–95
Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475:231–234
Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591
Song JH, Kandasamy K, Zemskova M, Lin Y-W, Kraft AS (2011) The BH3 mimetic ABT-737 induces cancer cell senescence. Cancer Res 71:506–515
Cruickshanks N, Tang Y, Booth L, Hamed H, Grant S, Dent P (2012) Lapatinib and Obatoclax kill breast cancer cells through reactive oxygen species-dependent endoplasmic reticulum stress. Mol Pharmacol 82:1217–1229
Zhang Z, Song T, Zhang T, Gao J, Wu G, An L, Du G (2011) A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1. Int J Cancer 128:1724–1735
Zhong JT, Xu Y, Yi HW, Su J, Yu HM, Xiang XY, Li XN, Zhang ZC, Sun LK (2012) The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells. Cancer Lett 323:180–187
Acknowledgments
This research was supported by a Translational Research Grant from the Leukemia and Lymphoma Society and a Cancer Center Support Grant to the Norris Cotton Cancer Center (NIH CA23108). Support to A.V.D. was provided by a National Cancer Institute new faculty award (NIH CA023108-31S4) to the Norris Cotton Cancer Center.
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Soderquist, R., Pletnev, A.A., Danilov, A.V. et al. The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA. Apoptosis 19, 201–209 (2014). https://doi.org/10.1007/s10495-013-0910-y
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DOI: https://doi.org/10.1007/s10495-013-0910-y