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Combinatorial Chemistry & High Throughput Screening

Author(s): Simin Yu, Zhuowang Ge, Weixiang Chen and Jinbin Han*

DOI: 10.2174/1386207326666230123155944

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Pyrrolidine Dithiocarbamate Enhances the Cytotoxic Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia Cells

Page: [2067 - 2076] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: More than 95% patients with acute promyelocytic leukemia (APL) carry the PML-RARα fusion oncoprotein. Arsenic trioxide (ATO) is an efficacious therapeutic agent for APL, and the mechanism involves the binding with PML and degradation of PML-RARα protein. Pyrrolidine dithiocarbamate (PDTC) demonstrates the function of facilitating the cytotoxic effect of ATO.

Purpose: To investigate whether PDTC is potential to enhance the cytotoxic effect of ATO to APL cells by acting on PML-RARα oncoproteins.

Methods: Inhibitory effects of drugs on cell viability were examined by CCK-8 test, and apoptosis was evaluated by flow cytometry. Western blotting and immunofluorescence assays were used to explore the mechanism.

Results: PDTC improved the effect of ATO on inhibiting proliferation of NB4 cells in vitro. Further, PDTC-ATO promoted apoptosis and cell cycle arrest in NB4 cells. The expression of caspase- 3 and Bcl-2 was reduced in PDTC-ATO-treated NB4 cells, while cleaved caspase-3 and Bax was up-regulated. Furthermore, less PML-RARα expression were found in PDTC-ATO-treated NB4 cells than that in NB4 cells treated with ATO singly. Laser confocal microscopy showed that protein colocalization of PML and RARα was disrupted more significantly by PDTC-ATO treatment than that with ATO monotherapy.

Conclusion: In conclusion, PDTC enhanced the cytotoxic effect of ATO on APL, and the mechanism was, at least in part, related to the promotion of ATO-induced degradation of PML-RARα fusion protein via forming a complex PDTC-ATO.

Graphical Abstract

[1]
Noguera, N.; Catalano, G.; Banella, C.; Divona, M.; Faraoni, I.; Ottone, T.; Arcese, W.; Voso, M. Acute promyelocytic leukemia: Update on the mechanisms of leukemogenesis, resistance and on innovative treatment strategies. Cancers (Basel), 2019, 11(10), 1591.
[http://dx.doi.org/10.3390/cancers11101591] [PMID: 31635329]
[2]
Moosavi, M.A.; Djavaheri-Mergny, M. Autophagy: New insights into mechanisms of action and resistance of treatment in acute promyelocytic leukemia. Int. J. Mol. Sci., 2019, 20(14), 3559.
[http://dx.doi.org/10.3390/ijms20143559] [PMID: 31330838]
[3]
Voisset, E.; Moravcsik, E.; Stratford, E.W.; Jaye, A.; Palgrave, C.J.; Hills, R.K.; Salomoni, P.; Kogan, S.C.; Solomon, E.; Grimwade, D. Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice. Blood, 2018, 131(6), 636-648.
[http://dx.doi.org/10.1182/blood-2017-07-794784] [PMID: 29191918]
[4]
Yousefnia, S. Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias. Cell Biol. Int., 2021, 45(6), 1148-1157.
[http://dx.doi.org/10.1002/cbin.11563] [PMID: 33527587]
[5]
Tan, Y.; Wang, X.; Song, H.; Zhang, Y.; Zhang, R.; Li, S.; Jin, W.; Chen, S.; Fang, H.; Chen, Z.; Wang, K.A. PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia. Blood, 2021, 137(11), 1503-1516.
[http://dx.doi.org/10.1182/blood.2020005698] [PMID: 32854112]
[6]
Kayser, S.; Schlenk, R.F.; Platzbecker, U. Management of patients with acute promyelocytic leukemia. Leukemia, 2018, 32(6), 1277-1294.
[http://dx.doi.org/10.1038/s41375-018-0139-4] [PMID: 29743722]
[7]
Sanz, M.A.; Fenaux, P.; Tallman, M.S.; Estey, E.H.; Löwenberg, B.; Naoe, T.; Lengfelder, E.; Döhner, H.; Burnett, A.K.; Chen, S.J.; Mathews, V.; Iland, H.; Rego, E.; Kantarjian, H.; Adès, L.; Avvisati, G.; Montesinos, P.; Platzbecker, U.; Ravandi, F.; Russell, N.H.; Lo-Coco, F. Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet. Blood, 2019, 133(15), 1630-1643.
[http://dx.doi.org/10.1182/blood-2019-01-894980] [PMID: 30803991]
[8]
Zhou, J.; Zhang, Y.; Li, J.; Li, X.; Hou, J.; Zhao, Y.; Liu, X.; Han, X.; Hu, L.; Wang, S.; Zhao, Y.; Zhang, Y.; Fan, S.; Lv, C.; Li, L.; Zhu, L. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood, 2010, 115(9), 1697-1702.
[http://dx.doi.org/10.1182/blood-2009-07-230805] [PMID: 20029047]
[9]
Zhang, X.W.; Yan, X.J.; Zhou, Z.R.; Yang, F.F.; Wu, Z.Y.; Sun, H.B.; Liang, W.X.; Song, A.X.; Lallemand-Breitenbach, V.; Jeanne, M.; Zhang, Q.Y.; Yang, H.Y.; Huang, Q.H.; Zhou, G.B.; Tong, J.H.; Zhang, Y.; Wu, J.H.; Hu, H.Y.; de Thé, H.; Chen, S.J.; Chen, Z. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science, 2010, 328(5975), 240-243.
[http://dx.doi.org/10.1126/science.1183424] [PMID: 20378816]
[10]
He, H.; An, R.; Hou, J.; Fu, W. Arsenic trioxide induced rhabdomyolysis, a rare but severe side effect, in an APL patient: a case report. Front. Med., 2017, 11(2), 284-286.
[http://dx.doi.org/10.1007/s11684-017-0514-y] [PMID: 28425042]
[11]
Chen, D.; Peng, F.; Cui, Q.C.; Daniel, K.G.; Orlu, S.; Liu, J.; Dou, Q.P. Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis. Front. Biosci., 2005, 10(1-3), 2932-2939.
[http://dx.doi.org/10.2741/1749] [PMID: 15970547]
[12]
Tahata, S.; Yuan, B.; Kikuchi, H.; Takagi, N.; Hirano, T.; Toyoda, H. Cytotoxic effects of pyrrolidine dithiocarbamate in small-cell lung cancer cells, alone and in combination with cisplatin. Int. J. Oncol., 2014, 45(4), 1749-1759.
[http://dx.doi.org/10.3892/ijo.2014.2564] [PMID: 25070243]
[13]
Wang, F.; Zhai, S.; Liu, X.; Li, L.; Wu, S.; Dou, Q.P.; Yan, B. A novel dithiocarbamate analogue with potentially decreased ALDH inhibition has copper-dependent proteasome-inhibitory and apoptosis-inducing activity in human breast cancer cells. Cancer Lett., 2011, 300(1), 87-95.
[http://dx.doi.org/10.1016/j.canlet.2010.09.010] [PMID: 21035945]
[14]
Ding, W.Q.; Yu, H.J.; Lind, S.E. Zinc-binding compounds induce cancer cell death via distinct modes of action. Cancer Lett., 2008, 271(2), 251-259.
[http://dx.doi.org/10.1016/j.canlet.2008.06.011] [PMID: 18639975]
[15]
Doerge, D.R.; Twaddle, N.C.; Churchwell, M.I.; Beland, F.A. Reduction by, ligand exchange among, and covalent binding to glutathione and cellular thiols link metabolism and disposition of dietary arsenic species with toxicity. Environ. Int., 2020, 144106086
[http://dx.doi.org/10.1016/j.envint.2020.106086] [PMID: 32889486]
[16]
Leslie, E.M. Arsenic–glutathione conjugate transport by the human multidrug resistance proteins (MRPs/ABCCs). J. Inorg. Biochem., 2012, 108, 141-149.
[http://dx.doi.org/10.1016/j.jinorgbio.2011.11.009] [PMID: 22197475]
[17]
Dai, J.; Weinberg, R.S.; Waxman, S.; Jing, Y. Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood, 1999, 93(1), 268-277.
[http://dx.doi.org/10.1182/blood.V93.1.268] [PMID: 9864170]
[18]
Lyczko, M.; Lyczko, K.; Majkowska-Pilip, A.; Bilewicz, A. 1,2-Benzenedithiol and toluene-3,4-dithiol arsenic(III) complexes-synthesis, structure, spectroscopic characterization and toxicological studies. Molecules, 2019, 24(21), 3865.
[http://dx.doi.org/10.3390/molecules24213865] [PMID: 31717768]
[19]
Yu, S.; Wu, N.; Zhu, J.; Liu, Y.; Han, J. Pyrrolidine dithiocarbamate facilitates arsenic trioxide against pancreatic cancer via perturbing ubiquitin-proteasome pathway. Cancer Manag. Res., 2020, 12, 13149-13159.
[http://dx.doi.org/10.2147/CMAR.S278674] [PMID: 33376406]
[20]
Meng, Q.; Peng, Z.; Chen, L.; Si, J.; Dong, Z.; Xia, Y. Nuclear Factor-κB modulates cellular glutathione and prevents oxidative stress in cancer cells. Cancer Lett., 2010, 299(1), 45-53.
[http://dx.doi.org/10.1016/j.canlet.2010.08.002] [PMID: 20810208]
[21]
Ganesan, S.; Alex, A.A.; Chendamarai, E.; Balasundaram, N.; Palani, H.K.; David, S.; Kulkarni, U.; Aiyaz, M.; Mugasimangalam, R.; Korula, A.; Abraham, A.; Srivastava, A.; Padua, R.A.; Chomienne, C.; George, B.; Balasubramanian, P.; Mathews, V. Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia, 2016, 30(11), 2169-2178.
[http://dx.doi.org/10.1038/leu.2016.227] [PMID: 27560113]
[22]
Sumi, D.; Suzukawa, K.; Himeno, S. Arsenic trioxide augments all-trans retinoic acid-induced differentiation of HL-60 cells. Life Sci., 2016, 149, 42-50.
[http://dx.doi.org/10.1016/j.lfs.2016.02.054] [PMID: 26892147]
[23]
Reyna, D.E.; Garner, T.P.; Lopez, A.; Kopp, F.; Choudhary, G.S.; Sridharan, A.; Narayanagari, S.R.; Mitchell, K.; Dong, B.; Bartholdy, B.A.; Walensky, L.D.; Verma, A.; Steidl, U.; Gavathiotis, E. Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia. Cancer Cell, 2017, 32(4), 490-505.e10.
[http://dx.doi.org/10.1016/j.ccell.2017.09.001] [PMID: 29017059]
[24]
Müller, S.; Matunis, M.J.; Dejean, A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J., 1998, 17(1), 61-70.
[http://dx.doi.org/10.1093/emboj/17.1.61] [PMID: 9427741]
[25]
Chen, J.; Tian, B.; Zhou, C.; Sun, J.; Lin, L.; Jin, S.; Liu, Q.; Fu, S.; Liu, L.; Liu, H.; Zhang, Z.; Li, C.; Wei, H. A novel resveratrol-arsenic trioxide combination treatment synergistically induces apoptosis of adriamycin-selected drug-resistant leukemia k562 cells. J. Cancer, 2019, 10(22), 5483-5493.
[http://dx.doi.org/10.7150/jca.34506] [PMID: 31632492]
[26]
Wang, Z.; Zhang, H.; Dai, L.; Song, T.; Li, P.; Liu, Y.; Wang, L. Arsenic trioxide and icariin show synergistic anti-leukemic activity. Cell Biochem. Biophys., 2015, 73(1), 213-219.
[http://dx.doi.org/10.1007/s12013-015-0660-2] [PMID: 25721870]
[27]
Liu, G.Y.; Frank, N.; Bartsch, H.; Lin, J.K. Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFκB c-fos/c-jun, and p53 proteins. Mol. Carcinog., 1998, 22(4), 235-246.
[http://dx.doi.org/10.1002/(SICI)1098-2744(199808)22:4<235:AID-MC5>3.0.CO;2-I] [PMID: 9726816]
[28]
Chabicovsky, M.; Prieschl-Grassauer, E.; Seipelt, J.; Muster, T.; Szolar, O.H.J.; Hebar, A.; Doblhoff-Dier, O. Pre-clinical safety evaluation of pyrrolidine dithiocarbamate. Basic Clin. Pharmacol. Toxicol., 2010, 107(3), 758-767.
[http://dx.doi.org/10.1111/j.1742-7843.2010.00573.x] [PMID: 20406205]
[29]
Chen, G.Q.; Shi, X.G.; Tang, W.; Xiong, S.M.; Zhu, J.; Cai, X.; Han, Z.G.; Ni, J.H.; Shi, G.Y.; Jia, P.M.; Liu, M.M.; He, K.L.; Niu, C.; Ma, J.; Zhang, P.; Zhang, T.D.; Paul, P.; Naoe, T.; Kitamura, K.; Miller, W.; Waxman, S.; Wang, Z.Y.; de The, H.; Chen, S.J.; Chen, Z. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood, 1997, 89(9), 3345-3353.
[PMID: 9129041]
[30]
Huang, S.; Wang, L.L.; Xue, N.N.; Li, C.; Guo, H.H.; Ren, T.K.; Zhan, Y.; Li, W.B.; Zhang, J.; Chen, X.G.; Han, Y.X.; Zhang, J.L.; Jiang, J.D. Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation. Theranostics, 2019, 9(23), 6745-6763.
[http://dx.doi.org/10.7150/thno.34674] [PMID: 31660066]
[31]
Yan, F.S.; Sun, J.L.; Xie, W.H.; Shen, L.; Ji, H.F. Neuroprotective effects and mechanisms of curcumin–Cu(II) and –Zn(II) complexes systems and their pharmacological implications. Nutrients, 2017, 10(1), 28.
[http://dx.doi.org/10.3390/nu10010028] [PMID: 29283372]
[32]
Hu, S.C.; Yang, J.; Chen, C.; Song, J.R.; Pan, W.D. Design, synthesis of novel tetrandrine-14-l-amino acid and tetrandrine-14-l-amino acid-urea derivatives as potential anti-cancer agents. Molecules, 2020, 25(7), 1738.
[http://dx.doi.org/10.3390/molecules25071738] [PMID: 32283819]
[33]
Bachleitner-Hofmann, T.; Kees, M.; Gisslinger, H. Arsenic trioxide: Acute promyelocytic leukemia and beyond. Leuk. Lymphoma, 2002, 43(8), 1535-1540.
[http://dx.doi.org/10.1080/1042819021000002857] [PMID: 12400595]
[34]
Ganesan, S.; Palani, H.K.; Lakshmanan, V.; Balasundaram, N.; Alex, A.A.; David, S.; Venkatraman, A.; Korula, A.; George, B.; Balasubramanian, P.; Palakodeti, D.; Vyas, N.; Mathews, V. Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia. Cell Death Dis., 2019, 10(10), 736.
[http://dx.doi.org/10.1038/s41419-019-1964-8] [PMID: 31570693]
[35]
Chen, Y.; Chen, L.; Yu, J.; Ghia, E.M.; Choi, M.Y.; Zhang, L.; Zhang, S.; Sanchez-Lopez, E.; Widhopf, G.F., II; Messer, K.; Rassenti, L.Z.; Jamieson, C.; Kipps, T.J. Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia. Blood, 2019, 134(13), 1084-1094.
[http://dx.doi.org/10.1182/blood.2019001366] [PMID: 31409670]