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Journal of Experimental & Clinical Cancer Research

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01-12-2020 | Multiple Myeloma | Research

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

Authors: Liangning Hu, Bo Li, Gege Chen, Dongliang Song, Zhijian Xu, Lu Gao, Mengyu Xi, Jinfeng Zhou, Liping Li, Hui Zhang, Qilin Feng, Yingcong Wang, Kang Lu, Yumeng Lu, Wenxuan Bu, Houcai Wang, Xiaosong Wu, Weiliang Zhu, Jumei Shi

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Abstract

Background

DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown.

Methods

We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models.

Results

DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G₂/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933.

Conclusions

Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

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Mujtaba T, Dou QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011;12(67):471–80.PubMedPubMedCentral

Twombly R. First proteasome inhibitor approved for multiple myeloma. J Natl Cancer Inst. 2003;95(12):845.PubMedCrossRef

Murray MY, Auger MJ, Bowles KM. Overcoming bortezomib resistance in multiple myeloma. Biochem Soc T. 2014;42(4):804–8.CrossRef

Ludwig H, Beksac M, Bladé J, Boccadoro M, Cavenagh J, Cavo M, Dimopoulos M, Drach J, Einsele H, Facon T, et al. Current multiple myeloma treatment strategies with novel agents: a European perspective. Oncologist. 2010;15(1):6–25.PubMedPubMedCentralCrossRef

Alimbetov D, Askarova S, Umbayev B, Davis T, Kipling D. Pharmacological targeting of cell cycle, apoptotic and cell adhesion signaling pathways implicated in Chemoresistance of Cancer cells. Int J Mol Sci. 2018;19(6):1690.PubMedCentralCrossRef

Johnsen HE, Bøgsted M, Schmitz A, Bødker JS, El-Galaly TC, Johansen P, Valent P, Zojer N, Van Valckenborgh E, Vanderkerken K, et al. The myeloma stem cell concept, revisited: from phenomenology to operational terms. Haematologica. 2016;101(12):1451–9.PubMedPubMedCentralCrossRef

Gao M, Kong Y, Yang G, Gao L, Shi J. Multiple myeloma cancer stem cells. Oncotarget. 2016;7(23):35466–77.PubMedPubMedCentralCrossRef

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.CrossRefPubMed

Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci. 2016;73(15):2829–50.PubMedCrossRef

10.

Chou WC, Hu LY, Hsiung CN, Shen CY. Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway. Carcinogenesis. 2015;36(8):832–40.PubMedCrossRef

11.

Kabeche L, Nguyen HD, Buisson R, Zou L. A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science (New York, N.Y.). 2018;359(6371):108–14.CrossRef

12.

Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112.PubMedCrossRef

13.

Sun X, Li B, Xie B, Xu Z, Chang G, Tao Y, Zhang Y, Chang S, Wang Y, Yu D, et al. DCZ3301, a novel cytotoxic agent, inhibits proliferation in diffuse large B-cell lymphoma via the STAT3 pathway. Cell Death Dis. 2017;8(10):e3111.PubMedPubMedCentralCrossRef

14.

Xiao W, Li B, Sun X, Yu D, Xie Y, Wu H, Chang S, Zhou Y, Wang H, Lan X, et al. DCZ3301, a novel aryl-guanidino inhibitor, induces cell apoptosis and cell cycle arrest via suppressing the PI3K/AKT pathway in T-cell leukemia/lymphoma. Acta Bioch Bioph Sin. 2018;50(7):643–50.CrossRef

15.

Gao M, Li B, Sun X, Zhou Y, Wang Y, Tompkins VS, Xu Z, Indima N, Wang H, Xiao W, et al. Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma. Theranostics. 2017;7(15):3690–9.PubMedPubMedCentralCrossRef

16.

Zhen N, Jin L, Ma J, Zhu J, Gu S, Wang J, Pan Q, Ni X, Xu M. Ginsenoside Rg1 impairs homologous recombination repair by targeting CtBP-interacting protein and sensitizes hepatoblastoma cells to DNA damage. Anti-Cancer Drugs. 2018;1(3):1.CrossRef

17.

Zhen N, Gu S, Ma J, Zhu J, Yin M, Xu M, Wang J, Huang N, Cui Z, Bian Z, et al. CircHMGCS1 promotes Hepatoblastoma cell proliferation by regulating the IGF signaling pathway and Glutaminolysis. Theranostics. 2019;9(3):900–19.PubMedPubMedCentralCrossRef

18.

Vignon C, Debeissat C, Georget MT, Bouscary D, Gyan E, Rosset P, Herault O. Flow cytometric quantification of all phases of the cell cycle and apoptosis in a two-color fluorescence plot. PLoS One. 2013;8(7):e68425.PubMedPubMedCentralCrossRef

19.

Walters DK, Wu X, Tschumper RC, Arendt BK, Huddleston PM, Henderson KJ, Dispenzieri A, Jelinek DF. Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX. Leukemia. 2011;25(8):1344–53.PubMedPubMedCentralCrossRef

20.

Robak P, Drozdz I, Szemraj J, Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018;70:199–208.PubMedCrossRef

21.

Denisenko TV, Sorokina IV, Gogvadze V, Zhivotovsky B. Mitotic catastrophe and cancer drug resistance: a link that must to be broken. Drug Resist Update. 2016;24:1–12.CrossRef

22.

Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440–6.PubMedCrossRef

23.

Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621–81.PubMedCrossRef

24.

Castellano-Pozo M, Santos-Pereira JM, Rondón AG, Barroso S, Andújar E, Pérez-Alegre M, García-Muse T, Aguilera A. R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Mol Cell. 2013;52(4):583–90.PubMedCrossRef

25.

McGowan CH. Checking in on Cds1 (Chk2): a checkpoint kinase and tumor suppressor. Bioessays. 2002;24(6):502–11.PubMedCrossRef

26.

Bartek J, Lukas J. DNA repair: damage alert. Nature. 2003;421(6922):486–8.PubMedCrossRef

27.

Bucher N, Britten CD. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Brit J Cancer. 2008;98(3):523–8.PubMedCrossRef

28.

Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol. 2006;18(2):185–91.PubMedCrossRef

29.

Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K, et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature. 2009;457(7225):57–62.PubMedCrossRef

30.

Afonso O, Castellani CM, Cheeseman LP, Ferreira JG, Orr B, Ferreira LT, Chambers JJ, Morais-de-Sa E, Maresca TJ, Maiato H. Spatiotemporal control of mitotic exit during anaphase by an Aurora B-Cdk1 crosstalk. Elife. 2019;8:e47646.

31.

Singh RP, Dhanalakshmi S, Agarwal R. Phytochemicals as cell cycle modulators--a less toxic approach in halting human cancers. Cell Cycle. 2002;1(3):156–61.PubMedCrossRef

32.

Poehlmann A, Habold C, Walluscheck D, Reissig K, Bajbouj K, Ullrich O, Hartig R, Gali-Muhtasib H, Diestel A, Roessner A, et al. Cutting edge: Chk1 directs senescence and mitotic catastrophe in recovery from G2 checkpoint arrest. J Cell Mol Med. 2011;15(7):1528–41.PubMedPubMedCentralCrossRef

33.

Meena SLPD. Regulation of DNA double-strand break repair pathway choice. Cell Res. 2008;18(1):134–47.CrossRef

34.

Pires E, Sung P, Wiese C. Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis. DNA Repair. 2017;59:76–81.PubMedPubMedCentralCrossRef

35.

On KF, Chen Y, Tang Ma H, Chow JPH, Poon RYC. Determinants of mitotic catastrophe on abrogation of the G2 DNA damage checkpoint by UCN-01. Mol Cancer Ther. 2011;10(5):784–94.PubMedCrossRef

36.

Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12(6):385–92.PubMedCrossRef

37.

Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004;23(16):2825–37.PubMedCrossRef

38.

Gu JJ, Kaufman GP, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells. Oncotarget. 2017;8(8):12741–53.PubMedCrossRef

Title: A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe
Authors: Liangning Hu
Bo Li
Gege Chen
Dongliang Song
Zhijian Xu
Lu Gao
Mengyu Xi
Jinfeng Zhou
Liping Li
Hui Zhang
Qilin Feng
Yingcong Wang
Kang Lu
Yumeng Lu
Wenxuan Bu
Houcai Wang
Xiaosong Wu
Weiliang Zhu
Jumei Shi
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Multiple Myeloma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-020-01597-9

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Abstract

Background

Methods

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