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01-12-2020 | Melanoma | Primary research

A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products

Authors: Keke Li, Shuang Zhao, Jing Long, Juan Su, Lisha Wu, Juan Tao, Jianda Zhou, JiangLin Zhang, Xiang Chen, Cong Peng

Published in: Cancer Cell International | Issue 1/2020

Abstract

Background

Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed, therefore, it is necessary to develop novel inhibitors for melanoma treatment.

Methods

We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma.

Results

We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells, revealing that this compound regulates various pathways, such as DNA replication, P53, apoptosis and the cell cycle. Additionally, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products, leading to DNA toxicity in melanoma cell lines. Moreover, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells, leading to DNA damage, which caused G2/M phase arrest and apoptosis.

Conclusions

Taken together, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels, suggesting that this compound is a potential therapeutic drug for melanoma treatment.

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Bu P, Yang P. MicroRNA-203 inhibits malignant melanoma cell migration by targeting versican. Exp Ther Med. 2014;8(1):309–15. https://doi.org/10.3892/etm.2014.1708.CrossRefPubMedPubMedCentral

Yang P, Bu P, Li C. miR-124 inhibits proliferation, migration and invasion of malignant melanoma cells via targeting versican. Exp Ther Med. 2017;14(4):3555–62. https://doi.org/10.3892/etm.2017.4998.CrossRefPubMedPubMedCentral

Kong Y, Si L, Zhu Y, Xu X, Corless CL, Flaherty KT, et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res. 2011;17(7):1684–91. https://doi.org/10.1158/1078-0432.CCR-10-2346.CrossRefPubMed

Long T, Su J, Tang W, Luo Z, Liu S, Liu Z, et al. A novel interaction between calcium-modulating cyclophilin ligand and Basigin regulates calcium signaling and matrix metalloproteinase activities in human melanoma cells. Cancer Lett. 2013;339(1):93–101. https://doi.org/10.1016/j.canlet.2013.07.019.CrossRefPubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.CrossRef

Xu D, Chen X, He Q, Luo C. MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1. Onco Targets Ther. 2016;9:7047–57. https://doi.org/10.2147/OTT.S107235.CrossRefPubMedPubMedCentral

Traylor JI, Kuo JS. Combined nivolumab and ipilimumab is an effective treatment for melanoma brain metastases. Neurosurgery. 2018. https://doi.org/10.1093/neuros/nyy619.CrossRef

Bu P, Luo C, He Q, Yang P, Li X, Xu D. MicroRNA-9 inhibits the proliferation and migration of malignant melanoma cells via targeting sirituin 1. Exp Ther Med. 2017;14(2):931–8. https://doi.org/10.3892/etm.2017.4595.CrossRefPubMedPubMedCentral

Liu N, Wang KS, Qi M, Zhou YJ, Zeng GY, Tao J, et al. Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels. J Exp Clin Cancer Res. 2018;37(1):269. https://doi.org/10.1186/s13046-018-0897-x.CrossRefPubMedPubMedCentral

10.

Alves-Fernandes DK, de Oliveira EA, Faiao-Flores F, Alicea-Rebecca G, Weeraratna AT, Smalley KSM, et al. ER stress promotes antitumor effects in BRAFi/MEKi resistant human melanoma induced by natural compound 4-nerolidylcathecol (4-NC). Pharmacol Res. 2018. https://doi.org/10.1016/j.phrs.2018.12.006.CrossRefPubMed

11.

Wu CE, Koay TS, Esfandiari A, Ho YH, Lovat P, Lunec J. ATM dependent DUSP6 modulation of p53 involved in synergistic targeting of MAPK and p53 pathways with trametinib and MDM2 inhibitors in cutaneous melanoma. Cancers. 2018. https://doi.org/10.3390/cancers11010003.CrossRefPubMedPubMedCentral

12.

Bommareddy PK, Aspromonte S, Zloza A, Rabkin SD, Kaufman HL. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Sci Transl Med. 2018. https://doi.org/10.1126/scitranslmed.aau0417.CrossRefPubMed

13.

Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, et al. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015;26(2):415–21. https://doi.org/10.1093/annonc/mdu529.CrossRefPubMed

14.

Desvignes C, Abi Rached H, Templier C, Drumez E, Lepesant P, Desmedt E, et al. BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response. Melanoma Res. 2017;27(3):281–7. https://doi.org/10.1097/CMR.0000000000000350.CrossRefPubMed

15.

Lee YH, Martin-Orozco N, Zheng P, Li J, Zhang P, Tan H, et al. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res. 2017;27(8):1034–45. https://doi.org/10.1038/cr.2017.90.CrossRefPubMedPubMedCentral

16.

Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011;16(1):5–24. https://doi.org/10.1634/theoncologist.2010-0190.CrossRefPubMedPubMedCentral

17.

Longoria TC, Eskander RN. Immune checkpoint inhibition: therapeutic implications in epithelial ovarian cancer. Recent Pat Anticancer Drug Discov. 2015;10(2):133–44.CrossRef

18.

Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015. https://doi.org/10.14694/edbook_am.2015.35.76.CrossRefPubMed

19.

Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 2015;37(4):764–82. https://doi.org/10.1016/j.clinthera.2015.02.018.CrossRefPubMedPubMedCentral

20.

Theurich S, Rothschild SI, Hoffmann M, Fabri M, Sommer A, Garcia-Marquez M, et al. Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma. Cancer Immunol Res. 2016;4(9):744–54. https://doi.org/10.1158/2326-6066.CIR-15-0156.CrossRefPubMed

21.

Cauwels A, Van Lint S, Garcin G, Bultinck J, Paul F, Gerlo S, et al. A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. Oncoimmunology. 2018;7(3):e1398876. https://doi.org/10.1080/2162402X.2017.1398876.CrossRefPubMed

22.

Yadav VR, Prasad S, Sung B, Aggarwal BB. The role of chalcones in suppression of NF-kappaB-mediated inflammation and cancer. Int Immunopharmacol. 2011;11(3):295–309. https://doi.org/10.1016/j.intimp.2010.12.006.CrossRefPubMed

23.

Zhu M, Wang J, Xie J, Chen L, Wei X, Jiang X, et al. Design, synthesis, and evaluation of chalcone analogues incorporate alpha, beta-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis. Eur J Med Chem. 2018;157:1395–405. https://doi.org/10.1016/j.ejmech.2018.08.072.CrossRefPubMed

24.

Bukhari SN, Jasamai M, Jantan I. Synthesis and biological evaluation of chalcone derivatives (mini review). Mini Rev Med Chem. 2012;12(13):1394–403.PubMed

25.

Singh P, Anand A, Kumar V. Recent developments in biological activities of chalcones: a mini review. Eur J Med Chem. 2014;85:758–77. https://doi.org/10.1016/j.ejmech.2014.08.033.CrossRefPubMed

26.

Warmka JK, Solberg EL, Zeliadt NA, Srinivasan B, Charlson AT, Xing C, et al. Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog. Biochem Biophys Res Commun. 2012;424(3):488–92. https://doi.org/10.1016/j.bbrc.2012.06.140.CrossRefPubMedPubMedCentral

27.

Xu S, Chen M, Chen W, Hui J, Ji J, Hu S, et al. Chemopreventive effect of chalcone derivative, L2H17, in colon cancer development. BMC Cancer. 2015;15:870. https://doi.org/10.1186/s12885-015-1901-x.CrossRefPubMedPubMedCentral

28.

Jandial DD, Krill LS, Chen L, Wu C, Ke Y, Xie J, et al. Induction of G2M arrest by flavokawain A, a kava chalcone, increases the responsiveness of HER2-overexpressing breast cancer cells to herceptin. Molecules. 2017. https://doi.org/10.3390/molecules22030462.CrossRefPubMedPubMedCentral

29.

Chen J, Peng C, Lei L, Zhang J, Zeng W, Chen X. Nuclear envelope-distributed CD147 interacts with and inhibits the transcriptional function of RING1 and promotes melanoma cell motility. PLoS ONE. 2017;12(8):e0183689. https://doi.org/10.1371/journal.pone.0183689.CrossRefPubMedPubMedCentral

30.

Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004;7(2):97–110. https://doi.org/10.1016/j.drup.2004.01.004.CrossRefPubMed

31.

Li R, Luo X, Zhu Y, Zhao L, Li L, Peng Q, et al. ATM signals to AMPK to promote autophagy and positively regulate DNA damage in response to cadmium-induced ROS in mouse spermatocytes. Environ Pollut. 2017;231(Pt 2):1560–8. https://doi.org/10.1016/j.envpol.2017.09.044.CrossRefPubMed

32.

Zhao H, Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol. 2001;21(13):4129–39. https://doi.org/10.1128/MCB.21.13.4129-4139.2001.CrossRefPubMedPubMedCentral

33.

Tu Y, Chen C, Pan J, Xu J, Zhou ZG, Wang CY. The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis. Int J Clin Exp Pathol. 2012;5(8):726–38.PubMedPubMedCentral

34.

Khattak M, Fisher R, Turajlic S, Larkin J. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol. 2013;5(2):105–18. https://doi.org/10.1177/1758834012466280.CrossRefPubMedPubMedCentral

35.

Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, et al. Roads to melanoma: key pathways and emerging players in melanoma progression and oncogenic signaling. Biochim Biophys Acta. 2016;1863(4):770–84. https://doi.org/10.1016/j.bbamcr.2016.01.025.CrossRefPubMed

36.

Margolin K. The promise of molecularly targeted and immunotherapy for advanced melanoma. Curr Treat Options Oncol. 2016;17(9):48. https://doi.org/10.1007/s11864-016-0421-5.CrossRefPubMed

37.

Griffin M, Scotto D, Josephs DH, Mele S, Crescioli S, Bax HJ, et al. BRAF inhibitors: resistance and the promise of combination treatments for melanoma. Oncotarget. 2017;8(44):78174–92. https://doi.org/10.18632/oncotarget.19836.CrossRefPubMedPubMedCentral

38.

Hatanaka M, Higashi Y, Kawai K, Su J, Zeng W, Chen X, et al. CD147-targeted siRNA in A375 malignant melanoma cells induces the phosphorylation of EGFR and downregulates cdc25C and MEK phosphorylation. Oncol Lett. 2016;11(4):2424–8. https://doi.org/10.3892/ol.2016.4267.CrossRefPubMedPubMedCentral

39.

Fulda S. Modulation of apoptosis by natural products for cancer therapy. Planta Med. 2010;76(11):1075–9. https://doi.org/10.1055/s-0030-1249961.CrossRefPubMed

40.

Funakoshi-Tago M, Tanabe S, Tago K, Itoh H, Mashino T, Sonoda Y, et al. Licochalcone A potently inhibits tumor necrosis factor alpha-induced nuclear factor-kappaB activation through the direct inhibition of IkappaB kinase complex activation. Mol Pharmacol. 2009;76(4):745–53. https://doi.org/10.1124/mol.109.057448.CrossRefPubMed

41.

Lee JS, Kang Y, Kim JT, Thapa D, Lee ES, Kim JA. The anti-angiogenic and anti-tumor activity of synthetic phenylpropenone derivatives is mediated through the inhibition of receptor tyrosine kinases. Eur J Pharmacol. 2012;677(1–3):22–30. https://doi.org/10.1016/j.ejphar.2011.12.012.CrossRefPubMed

42.

Phillips ER, McKinnon PJ. DNA double-strand break repair and development. Oncogene. 2007;26(56):7799–808. https://doi.org/10.1038/sj.onc.1210877.CrossRefPubMed

43.

Zhong G, Chen X, Fang X, Wang D, Xie M, Chen Q. Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway. Oncol Rep. 2016;35(1):447–53. https://doi.org/10.3892/or.2015.4395.CrossRefPubMed

44.

Tan ZH, Zhang Y, Tian Y, Tan W, Li YH. IkappaB kinase b mediating the downregulation of p53 and p21 by lipopolysaccharide in human papillomavirus 16(+) cervical cancer cells. Chin Med J. 2016;129(22):2703–7. https://doi.org/10.4103/0366-6999.193463.CrossRefPubMedPubMedCentral

45.

Xiao S, Zhou Y, Yi W, Luo G, Jiang B, Tian Q, et al. Fra-1 is downregulated in cervical cancer tissues and promotes cervical cancer cell apoptosis by p53 signaling pathway in vitro. Int J Oncol. 2015;46(4):1677–84. https://doi.org/10.3892/ijo.2015.2873.CrossRefPubMed

46.

Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13(12):1501–12.CrossRef

47.

Lei X, Liu B, Han W, Ming M, He YY. UVB-Induced p21 degradation promotes apoptosis of human keratinocytes. Photochem Photobiol Sci. 2010;9(12):1640–8. https://doi.org/10.1039/c0pp00244e.CrossRefPubMedPubMedCentral

48.

Yang W, Tang H, Zhang Y, Tang X, Zhang J, Sun L, et al. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am J Hum Genet. 2013;92(1):41–51. https://doi.org/10.1016/j.ajhg.2012.11.018.CrossRefPubMedPubMedCentral

49.

He Y, Yu B. MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells. Exp Ther Med. 2017;13(5):2003–11. https://doi.org/10.3892/etm.2017.4204.CrossRefPubMedPubMedCentral

50.

Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene. 2002;21(39):6017–31. https://doi.org/10.1038/sj.onc.1205877.CrossRefPubMed

51.

Fornace AJ Jr, Alamo I Jr, Hollander MC. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci USA. 1988;85(23):8800–4.CrossRef

52.

Abdollahi A, Lord KA, Hoffman-Liebermann B, Liebermann DA. Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines. Oncogene. 1991;6(1):165–7.PubMed

53.

Zhang W, Bae I, Krishnaraju K, Azam N, Fan W, Smith K, et al. CR6: a third member in the MyD118 and Gadd45 gene family which functions in negative growth control. Oncogene. 1999;18(35):4899–907. https://doi.org/10.1038/sj.onc.1202885.CrossRefPubMed

54.

Moskalev AA, Smit-McBride Z, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, et al. Gadd45 proteins: relevance to aging, longevity and age-related pathologies. Ageing Res Rev. 2012;11(1):51–66. https://doi.org/10.1016/j.arr.2011.09.003.CrossRefPubMed

55.

Bochman ML, Schwacha A. The Mcm complex: unwinding the mechanism of a replicative helicase. Microbiol Mol Biol Rev. 2009;73(4):652–83. https://doi.org/10.1128/MMBR.00019-09.CrossRefPubMedPubMedCentral

56.

Das M, Prasad SB, Yadav SS, Govardhan HB, Pandey LK, Singh S, et al. Over expression of minichromosome maintenance genes is clinically correlated to cervical carcinogenesis. PLoS ONE. 2013;8(7):e69607. https://doi.org/10.1371/journal.pone.0069607.CrossRefPubMedPubMedCentral

57.

Bailis JM, Forsburg SL. MCM proteins: DNA damage, mutagenesis and repair. Curr Opin Genet Dev. 2004;14(1):17–21. https://doi.org/10.1016/j.gde.2003.11.002.CrossRefPubMed

58.

Forsburg SL. Eukaryotic MCM proteins: beyond replication initiation. Microbiol Mol Biol Rev. 2004;68(1):109–31.CrossRef

59.

Mitchel RE, Hasu M, Bugden M, Wyatt H, Hildebrandt G, Chen YX, et al. Low-dose radiation exposure and protection against atherosclerosis in ApoE(−/−) mice: the influence of P53 heterozygosity. Radiat Res. 2013;179(2):190–9. https://doi.org/10.1667/RR3140.1.CrossRefPubMed

60.

Wang H, Luo Y, Zhao MH, Lin Z, Kwon J, Cui XS, et al. DNA double-strand breaks disrupted the spindle assembly in porcine oocytes. Mol Reprod Dev. 2016;83(2):132–43. https://doi.org/10.1002/mrd.22602.CrossRefPubMed

61.

Kastan MB, Lim DS. The many substrates and functions of ATM. Nat Rev Mol Cell Biol. 2000;1(3):179–86. https://doi.org/10.1038/35043058.CrossRefPubMed

62.

Brown EJ, Baltimore D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 2003;17(5):615–28. https://doi.org/10.1101/gad.1067403.CrossRefPubMedPubMedCentral

63.

Yin L, Liu Y, Peng Y, Peng Y, Yu X, Gao Y, et al. PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells. J Exp Clin Cancer Res. 2018;37(1):153. https://doi.org/10.1186/s13046-018-0810-7.CrossRefPubMedPubMedCentral

64.

Knight M, Raghavan N, Goodall C, Cousin C, Ittiprasert W, Sayed A, et al. Biomphalaria glabrata peroxiredoxin: effect of schistosoma mansoni infection on differential gene regulation. Mol Biochem Parasitol. 2009;167(1):20–31. https://doi.org/10.1016/j.molbiopara.2009.04.002.CrossRefPubMedPubMedCentral

65.

Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50–64. https://doi.org/10.1016/j.semcdb.2017.05.023.CrossRefPubMed

66.

Mittler R. ROS are good. Trends Plant Sci. 2017;22(1):11–9. https://doi.org/10.1016/j.tplants.2016.08.002.CrossRefPubMed

67.

Scialo F, Fernandez-Ayala DJ, Sanz A. Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease. Front Physiol. 2017;8:428. https://doi.org/10.3389/fphys.2017.00428.CrossRefPubMedPubMedCentral

Title: A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products
Authors: Keke Li
Shuang Zhao
Jing Long
Juan Su
Lisha Wu
Juan Tao
Jianda Zhou
JiangLin Zhang
Xiang Chen
Cong Peng
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Melanoma
Melanoma
Published in: Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-020-1114-5

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