Top

BMC Complementary Medicine and Therapies

Published in:

01-12-2021 | Prostate Cancer | Research article

Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

Authors: Ding-fang Zhang, Zhi-chun Yang, Jian-qiang Chen, Xiang-xiang Jin, Yin-da Qiu, Xiao-jing Chen, Hong-yi Shi, Zhi-guo Liu, Min-shan Wang, Guang Liang, Xiao-hui Zheng

Published in: BMC Complementary Medicine and Therapies | Issue 1/2021

Abstract

Background

Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes.

Methods

The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay.

Results

The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells.

Conclusion

Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

Available only for authorised users

Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. 2010;17(Suppl 2):S72–9.CrossRefPubMedPubMedCentral

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.CrossRefPubMed

Barry MJ, Simmons LH. Prevention of prostate Cancer morbidity and mortality: primary prevention and early detection. Med Clin North Am. 2017;101(4):787–806. https://doi.org/10.1016/j.mcna.2017.03.009.CrossRefPubMed

Berish RB, Ali AN, Telmer PG, Ronald JA, Leong HS. Translational models of prostate cancer bone metastasis. Nat Rev Urol. 2018;15(7):403–21. https://doi.org/10.1038/s41585-018-0020-2.CrossRefPubMed

de Oliveira Barros EG, Meireles Da Costa N, Palmero CY, et al. Malignant invasion of the central nervous system: the hidden face of a poorly understood outcome of prostate cancer. World J Urol. 2018;36(12):2009–19. https://doi.org/10.1007/s00345-018-2392-6.CrossRefPubMed

Dellis A, Zagouri F, Liontos M, et al. C management of advanced prostate cancer: a systematic review of existing guidelines and recommendations. Cancer Treat Rev. 2018;73:54–61.CrossRefPubMed

Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–94. https://doi.org/10.1038/nature10760.CrossRefPubMed

Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther. 2016;160:65–83. https://doi.org/10.1016/j.pharmthera.2016.02.003.CrossRefPubMedPubMedCentral

Krol M, Pawlowski KM, Majchrzak K, et al. Why chemotherapy can fail? Pol J Vet Sci. 2010;13(2):399–406.PubMed

10.

Reddy PS, Jamil K, Madhusudhan P, et al. Antibacterial activity of isolates from Piper longum and Taxus baccata. Pharm Biol. 2001;39(3):236–8. https://doi.org/10.1076/phbi.39.3.236.5926.CrossRef

11.

Bezerra DP, Pessoa C, Moraes MO, et al. In vivo growth inhibition of sarcoma 180 by piperlonguminine, an alkaloid amide from the Piper species. J Appl Toxicol. 2008;28(5):599–607. https://doi.org/10.1002/jat.1311.CrossRefPubMed

12.

Bezerra DP, Pessoa C, de Moraes MO, Saker-Neto N, Silveira ER, Costa-Lotufo LV. Overview of the therapeutic potential of piplartine (piperlongumine). Eur J Pharm Sci. 2013;48(3):453–63. https://doi.org/10.1016/j.ejps.2012.12.003.CrossRefPubMed

13.

Mohler H, Pfirrmann RW, Frei K. Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (review). Int J Oncol. 2014;45(4):1329–36. https://doi.org/10.3892/ijo.2014.2566.CrossRefPubMedPubMedCentral

14.

Ginzburg S, Golovine KV, Makhov PB, Uzzo RG, Kutikov A, Kolenko VM. Piperlongumine inhibits NF-kappaB activity and attenuates aggressive growth characteristics of prostate cancer cells. Prostate. 2014;74(2):177–86. https://doi.org/10.1002/pros.22739.CrossRefPubMed

15.

Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Adam A, Torres D, et al. Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene. 2015;34(11):1341–53. https://doi.org/10.1038/onc.2014.72.CrossRefPubMed

16.

Sun LD, Wang F, Dai F, Wang YH, Lin D, Zhou B. Development and mechanism investigation of a new piperlongumine derivative as a potent anti-inflammatory agent. Biochem Pharmacol. 2015;95(3):156–69. https://doi.org/10.1016/j.bcp.2015.03.014.CrossRefPubMed

17.

Matschke J, Riffkin H, Klein D, Handrick R, Lüdemann L, Metzen E, et al. Targeted inhibition of glutamine-dependent glutathione metabolism overcomes death resistance induced by chronic cycling hypoxia. Antioxid Redox Signal. 2016;25(2):89–107. https://doi.org/10.1089/ars.2015.6589.CrossRefPubMed

18.

Gu SM, Yun J, Son DJ, Kim HY, Nam KT, Kim HD, et al. Piperlongumine attenuates experimental autoimmune encephalomyelitis through inhibition of NF-kappaB activity. Free Radical Bio Med. 2017;103:133–45. https://doi.org/10.1016/j.freeradbiomed.2016.12.027.CrossRef

19.

Hang W, Yin ZX, Liu G, Zeng Q, Shen XF, Sun QH, et al. Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1. Oncogene. 2018;37(25):3384–98. https://doi.org/10.1038/s41388-017-0110-2.CrossRefPubMedPubMedCentral

20.

Piska K, Gunia-Krzyzak A, Koczurkiewicz P, et al. Piperlongumine (piplartine) as a lead compound for anticancer agents - synthesis and properties of analogues: a mini-review. Eur J Med Chem. 2018;156:13–20. https://doi.org/10.1016/j.ejmech.2018.06.057.CrossRefPubMed

21.

Golovine KV, Makhov PB, Teper E, Kutikov A, Canter D, Uzzo RG, et al. Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells. Prostate. 2013;73(1):23–30. https://doi.org/10.1002/pros.22535.CrossRefPubMed

22.

Piska K, Koczurkiewicz P, Wnuk D, Karnas E, Bucki A, Wójcik-Pszczoła K, et al. Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells - the involvement of carbonyl reductase 1 inhibition. Chem Biol Interact. 2019;300:40–8. https://doi.org/10.1016/j.cbi.2019.01.003.CrossRefPubMed

23.

Zheng XH, Zhong YF, Tan CP, Ji LN, Mao ZW. Pt(II) squares as selective and effective human telomeric G-quadruplex binders and potential cancer therapeutics. Dalton Trans. 2012;41(38):11807–12. https://doi.org/10.1039/c2dt31303k.CrossRefPubMed

24.

Zheng XH, Nie X, Liu HY, Fang YM, Zhao Y, Xia LX. TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses. Sci Rep. 2016;6(1):26592. https://doi.org/10.1038/srep26592.CrossRefPubMedPubMedCentral

25.

Zheng XH, Nie X, Fang Y, et al. A Cisplatin Derivative Tetra-Pt(bpy) as an Oncotherapeutic Agent for Targeting ALT Cancer. J Natl Cancer Inst. 2017;109(10):djx061.

26.

Chen YL, Deng ZQ, Jiang S, Hu Q, Liu H, Songyang Z, et al. Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance. Nucleic Acids Res. 2015;43(1):385–95. https://doi.org/10.1093/nar/gku1277.CrossRefPubMed

27.

Olive PL, Banath JP. The comet assay: a method to measure DNA damage in individual cells. Nat Protoc. 2006;1(1):23–9. https://doi.org/10.1038/nprot.2006.5.CrossRefPubMed

28.

Boyd D. Invasion and metastasis. Cancer Metastasis Rev. 1996;15(1):77–89. https://doi.org/10.1007/BF00049488.CrossRefPubMed

29.

Chugh P, Paluch EK. The actin cortex at a glance. J Cell Sci. 2018;131(14):jcs186254.

30.

Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nature reviews. Mol Cell Biol. 2005;6(1):56–68.

31.

Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G, Murcia JMD. Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem. 1998;273(50):33533–9. https://doi.org/10.1074/jbc.273.50.33533.CrossRefPubMed

32.

Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nature reviews. Drug Discov. 2017;16(4):273–84. https://doi.org/10.1038/nrd.2016.253.CrossRef

33.

Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16(1):20–33. https://doi.org/10.1038/nrc.2015.2.CrossRefPubMed

34.

Janic A, Valente LJ, Wakefield MJ, di Stefano L, Milla L, Wilcox S, et al. DNA repair processes are critical mediators of p53-dependent tumor suppression. Nat Med. 2018;24(7):947–53. https://doi.org/10.1038/s41591-018-0043-5.CrossRefPubMed

35.

Liu B, Yi J, Yang X, Liu L, Lou X, Zhang Z, et al. MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene. 2019;38(14):2501–15. https://doi.org/10.1038/s41388-018-0605-5.CrossRefPubMed

36.

Tang KJ, Constanzo JD, Venkateswaran N, Melegari M, Ilcheva M, Morales JC, et al. Focal adhesion kinase regulates the DNA damage response and its inhibition Radiosensitizes mutant KRAS lung Cancer. Clin Cancer Res. 2016;22(23):5851–63. https://doi.org/10.1158/1078-0432.CCR-15-2603.CrossRefPubMedPubMedCentral

37.

Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. 2019;25:101084. https://doi.org/10.1016/j.redox.2018.101084.CrossRefPubMed

38.

Filippo JS, Sung P, Klein H. Mechanism of eukaryotic homologous recombination. Annu Rev Biochem. 2008;77(1):229–57. https://doi.org/10.1146/annurev.biochem.77.061306.125255.CrossRef

39.

Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79(1):181–211. https://doi.org/10.1146/annurev.biochem.052308.093131.CrossRefPubMedPubMedCentral

40.

Nana FA, Vanderputten M, Ocak S. Role of focal adhesion kinase in small-cell lung cancer and its potential as a therapeutic target. Cancers. 2019;11(11):1683.CrossRef

41.

Karki K, Hedrick E, Kasiappan R, et al. Piperlongumine induces reactive oxygen species (ROS)-dependent downregulation of specificity protein transcription factors. Cancer Prev Res. 2017;10(8):467–77.CrossRef

Title: Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage
Authors: Ding-fang Zhang
Zhi-chun Yang
Jian-qiang Chen
Xiang-xiang Jin
Yin-da Qiu
Xiao-jing Chen
Hong-yi Shi
Zhi-guo Liu
Min-shan Wang
Guang Liang
Xiao-hui Zheng
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Prostate Cancer
Prostate Cancer
Published in: BMC Complementary Medicine and Therapies / Issue 1/2021
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-021-03369-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Yellow loosestrife (Lysimachia vulgaris var. davurica) ameliorates liver fibrosis in db/db mice with methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis

Lycium barbarum polysaccharides in ageing and its potential use for prevention and treatment of osteoarthritis: a systematic review

Facilitators and barriers to the clinical administration of herbal medicine in Ghana: a qualitative study

Synergistic antifungal evaluation of over-the-counter antifungal creams with turmeric essential oil or Aloe vera gel against pathogenic fungi

Evaluation of cholinesterase inhibitory and antioxidant activity of Wedelia chinensis and isolation of apigenin as an active compound

Inhibitory effects of Lactobacillus casei Shirota against both Candida auris and Candida spp. isolates that cause vulvovaginal candidiasis and are resistant to antifungals