Skip to main content
SpringerLink
Log in

(3,3’-Methylene)bis-2-hydroxy-1,4-naphthoquinones induce cytotoxicity against DU145 and PC3 cancer cells by inhibiting cell viability and promoting cell cycle arrest

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

We developed a novel method for the synthesis of bis-naphthoquinones (BNQ), which are hybrids of lawsone (2-hydroxy-1,4-naphthoquinone) and 3-hydroxy-juglone (3,5-dihydroxy-1,4-naphthoquinone). The anticancer activity of three synthesized compounds, named 4 (RC10), 5 (RCDFC), and 6 (RCDOH) was evaluated in vitro against two metastatic prostate cancer (PCa) cell lines, DU145 and PC3, using MTT assays. We found that 4 (RC10) and 5 (RCDFC) induced cytotoxicity against DU145 and PC3 cells. Flow cytometry analysis revealed that these two compounds promoted cell cycle arrest in G1/S and G2/M phases, increased Sub-G1 peak and induced inhibition in cell viability. We also showed that these effects are cell-type context dependent and more selective for these tested PCa cells than for HUVEC non-tumor cells. The two BNQ compounds 4 (RC10) and 5 (RCDFC) displayed promising anticancer activity against the two tested metastatic PCa cell lines, DU145 and PC3. Their effects are mainly associated with inhibition of cell viability, possibly through apoptotic cell death, besides altering the SubG1, G1/S and G2/M phases of cell cycle. 5 (RCDFC) compound was found to be more selective than 4 (RC10), when comparing their cytotoxic effects in relation to HUVEC non-tumoral cells. Future work should also test these compounds in combination with other chemotherapeutic drugs to evaluate their effects on further sensitizing drug-resistant metastatic PCa cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Raw data are readily available upon request.

References

  1. Rice MA, Malhotra SV, Stoyanova T (2019) Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front Oncol 9:801. https://doi.org/10.3389/fonc.2019.00801

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ferreira VF, Nicoletti CD, Ferreira PG, Futuro DO, da Silva F (2016) Strategies for Increasing the solubility and bioavailability of anticancer compounds: β-lapachone and other naphthoquinones. Curr Pharm Des 22(39):5899–5914. https://doi.org/10.2174/1381612822666160611012532

    Article  CAS  PubMed  Google Scholar 

  3. da Silva Júnior EN, Jardim GAM, Jacob C, Dhawa U, Ackermann L, de Castro SL (2019) Synthesis of quinones with highlighted biological applications: a critical update on the strategies towards bioactive compounds with emphasis on lapachones. Eur J Med Chem 179:863–915. https://doi.org/10.1016/j.ejmech.2019.06.056

    Article  CAS  PubMed  Google Scholar 

  4. Wellington KW (2015) Understanding cancer and the anticancer activities of naphthoquinones—a review. RSC Adv 5(26):20309–20338. https://doi.org/10.1039/C4RA13547D

    Article  CAS  Google Scholar 

  5. Chaudhary G, Goyal S, Poonia P (2010) Lawsonia inermis Linnaeus: a phytopharmacological review. Int J Pharm Sci Drug Res 2(2):91–98

    Google Scholar 

  6. Kamal M (2010) Pharmacological activities of lawsonia inermis Linn.: a review. Molecules 15(4):2139–51

    Article  Google Scholar 

  7. Abrams Motz V, Bowers CP, Mull Young L, Kinder DH (2012) The effectiveness of jewelweed, impatiens capensis, the related cultivar I. balsamina and the component, lawsone in preventing post poison ivy exposure contact dermatitis. J Ethnopharmacol 143(1):314–318. https://doi.org/10.1016/j.jep.2012.06.038

    Article  CAS  PubMed  Google Scholar 

  8. Dweck AC (2002) Natural ingredients for colouring and styling. Int J Cosmet Sci 24(5):287–302. https://doi.org/10.1046/j.1467-2494.2002.00148.x

    Article  CAS  PubMed  Google Scholar 

  9. Kosmalska A, Zaborski M, Masek A (2010) Naphthoquinone compounds as new antiageing substances for elastomers. Przem Chem 89(4):420–424

    CAS  Google Scholar 

  10. Pradhan R, Dandawate P, Vyas A, Padhye S, Biersack B, Schobert R, Sarkar FH (2012) From body art to anticancer activities: perspectives on medicinal properties of henna. Curr Drug Targets 13(14):1777–1798. https://doi.org/10.2174/138945012804545588

    Article  CAS  PubMed  Google Scholar 

  11. Rahmoun N, Boucherit-Otmani Z, Boucherit K, Benabdallah M, Choukchou-Braham N (2013) Antifungal activity of the Algerian Lawsonia inermis (henna). Pharm Biol 51(1):131–135. https://doi.org/10.3109/13880209.2012.715166

    Article  PubMed  Google Scholar 

  12. Habbal O, Hasson S, El-Hag A, Al-Mahrooqi Z, Al-Hashmi N, Al-Bimani Z et al (2011) Antibacterial activity of Lawsonia inermis linn (henna) against pseudomonas aeruginosa. Asian Pac J Trop Biomed 1(3):173–176. https://doi.org/10.1016/S2221-1691(11)60021-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rahmoun NM, Boucherit-Otmani Z, Boucherit K, Benabdallah M, Villemin D, Choukchou-Braham N (2012) Antibacterial and antifungal activity of lawsone and novel naphthoquinone derivatives. Medecine Et Maladies Infectieuses 42(6):270–275. https://doi.org/10.1016/j.medmal.2012.05.002

    Article  CAS  PubMed  Google Scholar 

  14. Futuro DO, Ferreira PG, Nicoletti CD, Borba-Santos LP, Silva FCD, Rozental S, Ferreira VF (2018) The antifungal activity of naphthoquinones: an integrative review. Anais Da Academia Brasileira De Ciencias 90(1 Suppl 2):1187–1214. https://doi.org/10.1590/0001-3765201820170815

    Article  CAS  PubMed  Google Scholar 

  15. Pereyra CE, Dantas RF, Ferreira SB, Gomes LP, Silva-Jr FP (2019) The diverse mechanisms and anticancer potential of naphthoquinones. Cancer Cell Int 19:207. https://doi.org/10.1186/s12935-019-0925-8

    Article  PubMed  PubMed Central  Google Scholar 

  16. Klotz L-O, Hou X, Jacob C (2014) 1,4-Naphthoquinones: from oxidative damage to cellular and inter-cellular signaling. Molecules 19(9):14902–14918. https://doi.org/10.3390/molecules190914902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jordão AK, Vargas MD, Pinto AC, da Silva F, Ferreira VF (2015) Lawsone in organic synthesis. RSC Adv 5(83):67909–67943. https://doi.org/10.1039/C5RA12785H

    Article  CAS  Google Scholar 

  18. Hamama WS, Hassanien AE-DE, Zoorob HH (2017) Advanced routes in synthesis and reactions of lawsone molecules (2-Hydroxynaphthalene-1,4-dione). J Heterocycl Chem 54(4):2155–2196. https://doi.org/10.1002/jhet.2855

    Article  CAS  Google Scholar 

  19. Oramas-Royo S, Torrejón C, Cuadrado I, Hernández-Molina R, Hortelano S, Estévez-Braun A, de las Heras B (2013) Synthesis and cytotoxic activity of metallic complexes of lawsone. Bioorg Med Chem 21(9):2471–2477. https://doi.org/10.1016/j.bmc.2013.03.002

    Article  CAS  PubMed  Google Scholar 

  20. Murakami K, Haneda M, Iwata S, Yoshino M (2010) Effect of hydroxy substituent on the prooxidant action of naphthoquinone compounds. Toxicol Vitro 24(3):905–909. https://doi.org/10.1016/j.tiv.2009.11.018

    Article  CAS  Google Scholar 

  21. Montenegro RC, Araújo AJ, Molina MT, Marinho Filho JDB, Rocha DD, Lopéz-Montero E et al (2010) Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative. Chem Biol Interact 184(3):439–448. https://doi.org/10.1016/j.cbi.2010.01.041

    Article  CAS  PubMed  Google Scholar 

  22. Monks TJ, Hanzlik RP, Cohen GM, Ross D, Graham DG (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112(1):2–16. https://doi.org/10.1016/0041-008x(92)90273-u

    Article  CAS  PubMed  Google Scholar 

  23. da Rocha DR, de Souza ACG, Resende JALC, Santos WC, dos Santos EA, Pessoa C et al (2011) Synthesis of new 9-hydroxy-α- and 7-hydroxy-β-pyran naphthoquinones and cytotoxicity against cancer cell lines. Org Biomol Chem 9(11):4315–4322. https://doi.org/10.1039/C1OB05209H

    Article  PubMed  Google Scholar 

  24. Fischer TC, Gosch C, Mirbeth B, Gselmann M, Thallmair V, Stich K (2012) Potent and specific bactericidal effect of juglone (5-hydroxy-1,4-naphthoquinone) on the fire blight pathogen erwinia amylovora. J Agric Food Chem 60(49):12074–12081. https://doi.org/10.1021/jf303584r

    Article  CAS  PubMed  Google Scholar 

  25. Babula P, Adam V, Kizek R, Sladký Z, Havel L (2009) Naphthoquinones as allelochemical triggers of programmed cell death. Environ Exp Bot 65(2):330–337. https://doi.org/10.1016/j.envexpbot.2008.11.007

    Article  CAS  Google Scholar 

  26. Amuthan G, Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG (2002) Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21(51):7839–7849. https://doi.org/10.1038/sj.onc.1205983

    Article  CAS  PubMed  Google Scholar 

  27. Xu HL, Yu XF, Qu SC, Qu XR, Jiang YF, Sui DY (2012) Juglone, from juglans mandshruica maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism. Food Chem Toxicol 50(3–4):590–596. https://doi.org/10.1016/j.fct.2012.01.002

    Article  CAS  PubMed  Google Scholar 

  28. Aithal BK, Kumar MRS, Rao BN, Udupa N, Rao BSS (2009) Juglone, a naphthoquinone from walnut, exerts cytotoxic and genotoxic effects against cultured melanoma tumor cells. Cell Biol Int 33(10):1039–1049. https://doi.org/10.1016/j.cellbi.2009.06.018

    Article  CAS  PubMed  Google Scholar 

  29. Ji YB, Xin GS, Qu ZY, Zou X, Yu M (2016) Mechanism of juglone-induced apoptosis of MCF-7 cells by the mitochondrial pathway. Genet Mol Res. https://doi.org/10.4238/gmr.15038785

    Article  PubMed  Google Scholar 

  30. Zhang W, Liu A, Li Y, Zhao X, Lv S, Zhu W, Jin Y (2012) Anticancer activity and mechanism of juglone on human cervical carcinoma HeLa cells. Can J Physiol Pharmacol 90(11):1553–1558. https://doi.org/10.1139/y2012-134

    Article  CAS  PubMed  Google Scholar 

  31. Fang F, Qin Y, Qi L, Fang Q, Zhao L, Chen S et al (2015) Juglone exerts antitumor effect in ovarian cancer cells. Iran J Basic Med Sci 18(6):544–548

    PubMed  PubMed Central  Google Scholar 

  32. Kacar S, Kar F, Hacioglu C, Kanbak G, Sahinturk V (2020) The effects of L-NAME on DU145 human prostate cancer cell line: a cytotoxicity-based study. Hum Exp Toxicol 39(2):182–193. https://doi.org/10.1177/0960327119880591

    Article  CAS  PubMed  Google Scholar 

  33. Lewinska A, Siwak J, Rzeszutek I, Wnuk M (2015) Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line. Toxicol Vitro 29(3):417–425. https://doi.org/10.1016/j.tiv.2014.12.005

    Article  CAS  Google Scholar 

  34. Namekawa T, Ikeda K, Horie-Inoue K, Inoue S (2019) Application of prostate cancer models for preclinical study: advantages and limitations of cell lines, patient-derived xenografts, and three-dimensional culture of patient-derived cells. Cells. https://doi.org/10.3390/cells8010074

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kanaoka R, Kushiyama A, Seno Y, Nakatsu Y, Matsunaga Y, Fukushima T et al (2015) Pin1 inhibitor juglone exerts anti-oncogenic effects on LNCaP and DU145 cells despite the patterns of gene regulation by Pin1 differing between these cell lines. PLoS ONE 10(6):e0127467. https://doi.org/10.1371/journal.pone.0127467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ribeiro RCB, de Freitas PP, Moreira CS, de Moraes LGC, de Moraes MG, da Silva FC et al (2020) A new strategy for the synthesis of nonsymmetrical 3,3’-(Aryl/alkyl-methylene)bis-2-hydroxy-1,4-naphthoquinones and their cytotoxic effects in PC3 prostate cancer cells. J Braz Chem Soc 31(2):288–297. https://doi.org/10.21577/0103-5053.20190172

    Article  CAS  Google Scholar 

  37. Jardim GAM, Lima DJB, Valença WO, Lima DJB, Cavalcanti BC, Pessoa C et al (2017) Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions. Molecules (Basel, Switzerland). https://doi.org/10.3390/molecules23010083

    Article  Google Scholar 

  38. Prasad CV, Nayak VL, Ramakrishna S, Mallavadhani UV (2018) Novel menadione hybrids: synthesis, anticancer activity, and cell-based studies. Chem Biol Drug Des 91(1):220–233. https://doi.org/10.1111/cbdd.13073

    Article  CAS  PubMed  Google Scholar 

  39. Lu C, Li Y, Deng J, Li S, Shen Y, Wang H, Shen Y (2013) Hygrocins C-G, cytotoxic naphthoquinone ansamycins from gdmAI-disrupted Streptomyces sp. LZ35. J Nat Prod 76(12):2175–2179. https://doi.org/10.1021/np400474s

    Article  CAS  PubMed  Google Scholar 

  40. Kanaan YM, White DF, Das JR, Berhe S, Bakare O, Kenguele H et al (2010) Cytotoxic effects of N-(3-chloro-1,4-dioxo 1,4-dihydro-naphthalen-2-yl)-benzamide on androgen-dependent and -independent prostate cancer cell lines. Anticancer Res 30(2):519–527

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Firouzi Niaki E, Van Acker T, Imre L, Nánási P, Tarapcsák S, Bacsó Z et al (2020) Interactions of cisplatin and daunorubicin at the chromatin level. Sci Rep 10(1):1107. https://doi.org/10.1038/s41598-020-57702-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kraus D, Reckenbeil J, Veit N, Kuerpig S, Meisenheimer M, Beier I et al (2018) Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation. Cell Oncol (Dordr) 41(5):485–494. https://doi.org/10.1007/s13402-018-0385-5

    Article  CAS  Google Scholar 

  43. Denel-Bobrowska M, Lukawska M, Oszczapowicz I, Marczak A (2016) Histological subtype of ovarian cancer as a determinant of sensitivity to formamidine derivatives of doxorubicin - in vitro comparative studies with SKOV-3 and ES-2 cancer cell lines. Asian Pac J Cancer Prev 17(9):4223–4231

    CAS  PubMed  Google Scholar 

  44. Wang F, Yao X, Zhang Y, Tang J (2019) Synthesis, biological function and evaluation of shikonin in cancer therapy. Fitoterapia 134:329–339. https://doi.org/10.1016/j.fitote.2019.03.005

    Article  CAS  PubMed  Google Scholar 

  45. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52(6):1213–1225. https://doi.org/10.1016/j.yjmcc.2012.03.006

    Article  CAS  PubMed  Google Scholar 

  46. Pardee AB, Boorstein RJ, Lau CC (1983) Interference with DNA repair mechanisms of mammalian cells: cell cycle dependence. Princess Takamatsu Symp 13:287–294

    CAS  PubMed  Google Scholar 

  47. Pienta KJ (2001) Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol 28(4 Suppl 15):3–7. https://doi.org/10.1016/s0093-7754(01)90148-4

    Article  CAS  PubMed  Google Scholar 

  48. Wiench B, Chen Y-R, Paulsen M, Hamm R, Schröder S, Yang N-S, Efferth T (2013) Integration of different “-omics” technologies identifies inhibition of the IGF1R-Akt-mTOR signaling cascade involved in the cytotoxic effect of shikonin against leukemia cells. Evid Based Complement Alternat Med 2013:818709. https://doi.org/10.1155/2013/818709

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tisseh ZN, Bazgir A (2009) An efficient, clean synthesis of 3,3′-(arylmethylene)bis(2-hydroxynaphthalene-1,4-dione) derivatives. Dyes Pigm 83(2):258–261. https://doi.org/10.1016/j.dyepig.2008.09.003

    Article  CAS  Google Scholar 

  50. Sabutskii YE, Polonik SG, Denisenko VA, Dmitrenok PS (2014) A new method for thiomethylation of hydroxy-1, 4-naphthoquinones with n-acetyl-l-cysteine; first synthesis of fibrostatins B, C, and D. Synthesis 46(20):2763–2770

    Article  CAS  Google Scholar 

Download references

Funding

This research was funded by CNPq, CAPES and FAPERJ. FAPERJ Grant Nos. E-26/201.448/2014, E-26/E-26/111.227/2014; 210.394/2014; E-26/010.002007/2014; E-26/203.204/2015; E-26/203.006/2018;.CNPq Grant No. 310591/2014-7 and 312158/2017-3; FCT/CAPES Grant No. 99999.008550/2014-00; Ministério da Saúde and Programa de Oncobiologia/UFRJ, Grant Nos. not applicable. The author thanks FIOCRUZ for the HRESIMS, Grant Nos. not applicable.

Author information

Authors and Affiliations

  1. Instituto Nacional de Câncer, Coordenação de Pesquisa, Centro, Rio de Janeiro, RJ, 20231-050, Brazil

    Paula Priscilla de Freitas & Etel Rodrigues Pereira Gimba

  2. Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil

    Ruan Carlos Busquet Ribeiro, Caroline S. Moreira, David R. Rocha & Fernando de Carvalho da Silva

  3. Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Laboratório de Pesquisa Translacional, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil

    Isabella dos Santos Guimarães

  4. Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Santa Rosa, Niterói, RJ, 24241-002, Brazil

    Vitor Francisco Ferreira

  5. Departamento de Ciências da Natureza, Instituto de Humanidade E Saúde (IHS), Universidade Federal Fluminense, Campus de Rio das Ostras, Rio das Ostras, RJ, 28880-00, Brazil

    Etel Rodrigues Pereira Gimba

  6. Programa de Pós Graduação Stricto Sensu em Oncologia, Instituto Nacional de Câncer, Centro, Rio de Janeiro, RJ, 20231-050, Brazil

    Etel Rodrigues Pereira Gimba

  7. Programa de Pós Graduação em Ciências Biomédicas-Fisiologia E Farmacologia, Instituto Biomédico, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil

    Etel Rodrigues Pereira Gimba

Authors
  1. Paula Priscilla de Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruan Carlos Busquet Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabella dos Santos Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Caroline S. Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David R. Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fernando de Carvalho da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vitor Francisco Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Etel Rodrigues Pereira Gimba
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: PPF, RCB, ERPG, R, and VFF; Methodology: PPF, RCB, ISG, CSM and DRR; software: RCB and ISG; Validation: PPF and ISG; Formal analysis: PPF, ISG and ERPG; Investigation: PPF, RCB, ISG, and ERPG; Resources: ERPG and VFF; Data curation: PPF, RCB, ISG and ERPG; Writing—original draft preparation: ERPG, ISG and VFF; writing—review and editing: ERPG, ISG, VFF and FCS; Visualization: ERPG, ISG, PPF; Supervision: ERPG and VFF; Project administration: ERPG and VFF; Funding acquisition: ERPG, VFF; All authors have read and agreed on the final version of the manuscript.

Corresponding author

Correspondence to Etel Rodrigues Pereira Gimba.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Paula Priscilla de Freitas, Ruan Carlos Busquet Ribeiro, Isabella dos Santos Guimarães should be considered joint first author; Vitor Francisco Ferreira, Etel Rodrigues Pereira Gimba ERP should be considered joint senior authors

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 73 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Freitas, P.P., Ribeiro, R.C.B., dos Santos Guimarães, I. et al. (3,3’-Methylene)bis-2-hydroxy-1,4-naphthoquinones induce cytotoxicity against DU145 and PC3 cancer cells by inhibiting cell viability and promoting cell cycle arrest. Mol Biol Rep 48, 3253–3263 (2021). https://doi.org/10.1007/s11033-021-06406-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06406-w

Keywords

Search

Navigation