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image of Anticancer Properties of Phenylboronic Acid in Androgen-Dependent (LNCaP) and Androgen-Independent (PC3) Prostate Cancer Cells via MAP Kinases by 2D and 3D Culture Methods

Abstract

Objective

This study utilized three cell lines: normal prostate epithelial RWPE-1, androgen-dependent LNCaP, and androgen-independent PC3. We investigated the inhibitory effects of phenylboronic acid (PBA)’s inhibitory effect on cellular proliferation due to its ability to disrupt microtubule formation in prostate cancer cell lines. Additionally, this study aimed to assess the cytotoxic effects of PBA on prostate cancer cells using two-dimensional (2D) and three-dimensional (3D) cell culture models.

Methods

The IC50 values of PBA and colchicine were determined through viability assays in 2D and 3D models. Colony formation, proliferation, and migration assays were conducted. Immunofluorescence intensity analysis of MAPKKK proteins (ERK, JNK, p38) was performed to explore the mechanism of cellular response to PBA.

Results

The IC50 values were determined for each treatment group. After 48-hour of PBA treatment, migration was inhibited more effectively than with colchicine in both cancer cell lines. After 24-hour, PBA reduced colony formation and proliferation. PBA treatment for 24-hour decreased JNK expression in PC3 and LNCaP cells in 2D models. Both PBA and colchicine increased p38 expression in PC3 spheroids. PBA’s effects on cell deformation were visualized in semi-thin sections, marking the first ultrastructural observation of PBA-induced morphological defects in cancer cells.

Conclusion

PBA exerts antimitotic effects by inhibiting proliferation and migration and triggers diverse metabolic responses across different cell lines. Furthermore the low toxicity of PBA’s low toxicity on RWPE-1 cells suggests its potential as a promising chemotherapeutic agent for future studies.

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2025-01-20
2025-03-29

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References

  1. Siegel R.L. Giaquinto A.N. Jemal A. Cancer statistics, 2024. CA Cancer J. Clin. 2024 74 1 12 49 10.3322/caac.21820 38230766
    [Google Scholar]
  2. Harris A.E. Metzler V.M. Roy L.J. Varun D. Woodcock C.L. Haigh D.B. Endeley C. Haque M. Toss M.S. Alsaleem M. Persson J.L. Gudas L.J. Rakha E. Robinson B.D. Khani F. Martin L.M. Moyer J.E. Brownlie J. Madhusudan S. Allegrucci C. James V.H. Rutland C.S. Fray R.G. Ntekim A. Brot d.S. Mongan N.P. Jeyapalan J.N. Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer. Front. Endocrinol. 2022 13 1006101 10.3389/fendo.2022.1006101 36263323
    [Google Scholar]
  3. Ferraldeschi R. Welti J. Luo J. Attard G. Bono d.J.S. Targeting the androgen receptor pathway in castration-resistant prostate cancer: Progresses and prospects. Oncogene 2015 34 14 1745 1757 10.1038/onc.2014.115 24837363
    [Google Scholar]
  4. Shafi A.A. Yen A.E. Weigel N.L. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol. Ther. 2013 140 3 223 238 10.1016/j.pharmthera.2013.07.003 23859952
    [Google Scholar]
  5. Palmberg C. Koivisto P. Visakorpi T. Tammela T.L.J. PSA decline is an independent prognostic marker in hormonally treated prostate cancer. Eur. Urol. 1999 36 3 191 196 10.1159/000067996 10450001
    [Google Scholar]
  6. Saraon P. Drabovich A.P. Jarvi K.A. Diamandis E.P. Mechanisms of androgen-independent prostate cancer. EJIFCC 2014 25 1 42 54 27683456
    [Google Scholar]
  7. Chandrasekar T. Yang J.C. Gao A.C. Evans C.P. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl. Androl. Urol. 2015 4 3 365 380 10.3978/J.ISSN.2223‑4683.2015.05.02 26814148
    [Google Scholar]
  8. Türk C Neisius A Petrik A EAU guidelines on interventional treatment for urolithiasis. Europ. Urol. 2016 69 3 475 482
    [Google Scholar]
  9. Ramjan A Hossain M Runa JF Md H Mahmodul I Evaluation of thrombolytic potential of three medicinal plants available in Bangladesh, as a potent source of thrombolytic compounds. Avicenna. J. Phytomed. 2014 4 6 430 436 25386407
    [Google Scholar]
  10. George K. Thomas N.S. Malathi R. Modulatory effect of selected dietary phytochemicals on delayed rectifier K+ current in human prostate cancer cells. J. Membr. Biol. 2019 252 2-3 195 206 10.1007/s00232‑019‑00070‑9 31165179
    [Google Scholar]
  11. Page L.C. Koumakpayi I.H. Fahmy A.M. Masson M.A-M. Saad F. Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. Br. J. Cancer 2006 94 12 1906 1912 10.1038/sj.bjc.6603184 16721361
    [Google Scholar]
  12. Berish RB Ali AN Telmer PG Ronald JA Leong HS Translational models of prostate cancer bone metastasis. Nat. Rev. Urol. 2018 15 403 421 10.1038/s41585‑018‑0020‑2
    [Google Scholar]
  13. Wang Y. Xia Y. Lu Z. Metabolic features of cancer cells. Cancer Commun. 2018 38 1 1 6 10.1186/s40880‑018‑0335‑7 30376896
    [Google Scholar]
  14. Murphy B.T. MacKinnon S.L. Yan X. Hammond G.B. Vaisberg A.J. Neto C.C. Identification of triterpene hydroxycinnamates with in vitro antitumor activity from whole cranberry fruit (Vaccinium macrocarpon). J. Agric. Food Chem. 2003 51 12 3541 3545 10.1021/jf034114g 12769521
    [Google Scholar]
  15. Li X. Wang X. Zhang J. Hanagata N. Wang X. Weng Q. Ito A. Bando Y. Golberg D. Hollow boron nitride nanospheres as boron reservoir for prostate cancer treatment. Nat. Commun. 2017 8 1 13936 10.1038/ncomms13936 28059072
    [Google Scholar]
  16. Marasovic M. Ivankovic S. Stojkovic R. Djermic D. Galic B. Milos M. In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells. J. Enzyme Inhib. Med. Chem. 2017 32 1 1299 1304 10.1080/14756366.2017.1384823 29072095
    [Google Scholar]
  17. Williams G.M.T. Chapin R.E. King P.E. Moser G.J. Goldsworthy T.L. Morrison J.P. Maronpot R.R. Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. Toxicol. Pathol. 2004 32 1 73 78 10.1080/01926230490260899 14713551
    [Google Scholar]
  18. Barranco W.T. Hudak P.F. Eckhert C.D. Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States). Canc. Caus. Cont. 2007 18 1 71 77 10.1007/s10552‑006‑0077‑8 17186423
    [Google Scholar]
  19. McAuley E.M. Bradke T.A. Plopper G.E. Phenylboronic acid is a more potent inhibitor than boric acid of key signaling networks involved in cancer cell migration. Cell Adhes. Migr. 2011 5 5 382 386 10.4161/cam.5.5.18162 21975546
    [Google Scholar]
  20. Psurski M. Słowik Ł.A. Woźniak A.A. Wietrzyk J. Sporzyński A. Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology – phase cycle-specific inducers of apoptosis in A2780 ovarian cancer cells. Invest. New Drugs 2019 37 1 35 46 10.1007/s10637‑018‑0611‑z 29779163
    [Google Scholar]
  21. Kaur R. Kaur G. Gill R.K. Soni R. Bariwal J. Recent developments in tubulin polymerization inhibitors: An overview. Eur. J. Med. Chem. 2014 87 89 124 10.1016/j.ejmech.2014.09.051 25240869
    [Google Scholar]
  22. Qin M. Peng S. Liu N. Hu M. He Y. Li G. Chen H. He Y. Chen A. Wang X. Liu M. Chen Y. Yi Z. LG308, a novel synthetic compound with antimicrotubule activity in prostate cancer cells, exerts effective antitumor activity. J. Pharmacol. Exp. Ther. 2015 355 3 473 483 10.1124/jpet.115.225912 26377911
    [Google Scholar]
  23. Mukhtar E. Adhami V.M. Sechi M. Mukhtar H. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett. 2015 367 2 173 183 10.1016/j.canlet.2015.07.030 26235140
    [Google Scholar]
  24. Bates D. Eastman A. Microtubule destabilising agents: Far more than just antimitotic anticancer drugs. Br. J. Clin. Pharmacol. 2017 83 2 255 268 10.1111/bcp.13126 27620987
    [Google Scholar]
  25. Stone A.A. Chambers T.C. Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signaling pathways in human KB-3 carcinoma cells. Exp. Cell Res. 2000 254 1 110 119 10.1006/excr.1999.4731 10623471
    [Google Scholar]
  26. Shtil AA Mandlekar S Yu R Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. Oncogene 1999 18 2 377 384 10.1038/sj.onc.1202305
    [Google Scholar]
  27. Barranco W.T. Eckhert C.D. Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br. J. Cancer 2006 94 6 884 890 10.1038/sj.bjc.6603009 16495920
    [Google Scholar]
  28. Oh J. An H.J. Yeo H.J. Choi S. Oh J. Kim S. Kim J.M. Choi J. Lee S. Colchicine as a novel drug for the treatment of osteosarcoma through drug repositioning based on an FDA drug library. Front. Oncol. 2022 12 893951 10.3389/fonc.2022.893951 36059694
    [Google Scholar]
  29. Kurek J Myszkowski K Kozaryn O.I Cytotoxic, analgesic and anti-inflammatory activity of colchicine and its C-10 sulfur containing derivatives. Sci. Rep. 2021 11 1 1 12 10.1038/s41598‑021‑88260‑1
    [Google Scholar]
  30. Bradke T.M. Hall C. Carper S.W. Plopper G.E. Phenylboronic acid selectively inhibits human prostate and breast cancer cell migration and decreases viability. Cell Adhes. Migr. 2008 2 3 153 160 10.4161/cam.2.3.6484 19262119
    [Google Scholar]
  31. Rolfo A. Giuffrida D. Giuffrida M.C. Todros T. Calogero A.E. New perspectives for prostate cancer treatment: In vitro inhibition of LNCaP and PC3 cell proliferation by amnion-derived mesenchymal stromal cells conditioned media. Aging Male 2014 17 2 94 101 10.3109/13685538.2014.896894 24597941
    [Google Scholar]
  32. Gannon P.O. Ethier G.J. Hassler M. Delvoye N. Aversa M. Poisson A.O. Péant B. Fahmy A.M. Saad F. Lapointe R. Masson M.A.M. Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer. PLoS One 2010 5 8 e12107 10.1371/journal.pone.0012107 20711410
    [Google Scholar]
  33. Shen R. Sumitomo M. Dai J. Harris A. Kaminetzky D. Gao M. Burnstein K.L. Nanus D.M. Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Endocrinology 2000 141 5 1699 1704 10.1210/endo.141.5.7463 10803579
    [Google Scholar]
  34. Laurenzana A. Balliu M. Cellai C. Romanelli M.N. Paoletti F. Effectiveness of the histone deacetylase inhibitor (S)-2 against LNCaP and PC3 human prostate cancer cells. PLoS One 2013 8 3 e58267 10.1371/journal.pone.0058267 23469273
    [Google Scholar]
  35. Sintich S.M. Steinberg J. Kozlowski J.M. Cytotoxic sensitivity to tumor necrosis factor-in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2. Clusterin 1999 39 2 87 93
    [Google Scholar]
  36. Bello D. Webber M.M. Kleinman H.K. Wartinger D.D. Rhim J.S. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis 1997 18 6 1215 1223 10.1093/carcin/18.6.1215 9214605
    [Google Scholar]
  37. Webber M. Bello D. Kleinman H.K. Hoffman M.P. Acinar differentiation by non-malignant immortalized human prostatic epithelial cells and its loss by malignant cells. Carcinogenesis 1997 18 6 1225 1231 10.1093/carcin/18.6.1225 9214606
    [Google Scholar]
  38. Achanzar W.E. Achanzar K.B. Lewis J.G. Webber M.M. Waalkes M.P. Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis. Toxicol. Appl. Pharmacol. 2000 164 3 291 300 10.1006/taap.1999.8907 10799339
    [Google Scholar]
  39. Quader S.T.A. DeOcampo B.D. Williams D.E. Kleinman H.K. Webber M.M. Evaluation of the chemopreventive potential of retinoids using a novel in vitro human prostate carcinogenesis model. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2001 496 1-2 153 161 10.1016/S1383‑5718(01)00230‑3 11551491
    [Google Scholar]
  40. Bulbul M. Karabulut S. Kalender M. Keskin I. Effects of gallic acid on endometrial cancer cells in two and three dimensional cell culture models. Asian Pac. J. Cancer Prev. 2021 22 6 1745 1751 10.31557/APJCP.2021.22.6.1745 34181329
    [Google Scholar]
  41. Martinotti S. Ranzato E. Scratch wound healing assay. Methods Mol. Biol. 2019 2109 225 229 10.1007/7651_2019_259 31414347
    [Google Scholar]
  42. Banerjee A. Biswas R. Lim R. Pasolli H.A. Raghavan S. Scanning electron microscopy of murine skin ultrathin sections and cultured keratinocytes. STAR Protoc. 2021 2 3 100729 10.1016/j.xpro.2021.100729 34458866
    [Google Scholar]
  43. Finkelstein Y. Aks S.E. Hutson J.R. Juurlink D.N. Nguyen P. Raz D.G. Pollak U. Koren G. Bentur Y. Colchicine poisoning: The dark side of an ancient drug. Clin. Toxicol. 2010 48 5 407 414 10.3109/15563650.2010.495348 20586571
    [Google Scholar]
  44. Liu L. Chen M. Gao Y. Tian L. Zhang W. Wang Z. Mechanism of action and side effects of colchicine based on biomechanical properties of cells. J. Microsc. 2023 291 3 229 236 10.1111/jmi.13212 37358710
    [Google Scholar]
  45. Carr A.A. Colchicine toxicity. Arch. Intern. Med. 1965 115 1 29 33 10.1001/archinte.1965.03860130031005 14219498
    [Google Scholar]
  46. Eleftheriou G. Bacis G. Fiocchi R. Sebastiano R. Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. Clin. Toxicol. 2008 46 9 827 830 10.1080/15563650701779703 18608282
    [Google Scholar]
  47. Fisher M.F. Rao S.S. Three‐dimensional culture models to study drug resistance in breast cancer. Biotechnol. Bioeng. 2020 117 7 2262 2278 10.1002/bit.27356 32297971
    [Google Scholar]
  48. Kaushik V. Yakisich J.S. Way L.F. Azad N. Iyer A.K.V. Chemoresistance of cancer floating cells is independent of their ability to form 3D structures: Implications for anticancer drug screening. J. Cell. Physiol. 2019 234 4 4445 4453 10.1002/jcp.27239 30191978
    [Google Scholar]
  49. Veine DM Yao H Stafford DR Fay KS Livant DL A D-amino acid containing peptide as a potent, noncovalent inhibitor of α5β1 integrin in human prostate cancer invasion and lung colonization. Clin Exp Metastasis. 2014 31 4 379 393 10.1007/s10585‑013‑9634‑1
    [Google Scholar]
  50. Abel S.D.A. Dadhwal S. Gamble A.B. Baird S.K. Honey reduces the metastatic characteristics of prostate cancer cell lines by promoting a loss of adhesion. PeerJ 2018 6 7 e5115 10.7717/peerj.5115 30002964
    [Google Scholar]
  51. Schatten H. Brief overview of prostate cancer statistics, grading, diagnosis and treatment strategies. Adv. Exp. Med. Biol. 2018 1095 1 14 10.1007/978‑3‑319‑95693‑0_1 30229546
    [Google Scholar]
  52. Dehghani M Kianpour S Zangeneh A Pour M.Z. CXCL12 Modulates Prostate Cancer Cell Adhesion by Altering the Levels or Activities of β1-Containing Integrins. Int J Cell Biol 2014 2014 981750 10.1155/2014/981750
    [Google Scholar]
  53. Kennedy N.J. Davis R.J. Role of JNK in tumor development. Cell Cycle 2003 2 3 198 200 10.4161/cc.2.3.388 12734425
    [Google Scholar]
  54. Weston C. Davis R.J. The JNK signal transduction pathway. Curr. Opin. Genet. Dev. 2002 12 1 14 21 10.1016/S0959‑437X(01)00258‑1 11790549
    [Google Scholar]
  55. Eferl R. Ricci R. Kenner L. Zenz R. David J.P. Rath M. Wagner E.F. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 2003 112 2 181 192 10.1016/S0092‑8674(03)00042‑4 12553907
    [Google Scholar]
  56. Xu R. Hu J. The role of JNK in prostate cancer progression and therapeutic strategies. Biomed. Pharmacother. 2020 121 109679 10.1016/j.biopha.2019.109679 31810118
    [Google Scholar]
  57. Kolomeichuk S.N. Terrano D.T. Lyle C.S. Sabapathy K. Chambers T.C. Distinct signaling pathways of microtubule inhibitors – vinblastine and Taxol induce JNK‐dependent cell death but through AP‐1‐dependent and AP‐1‐independent mechanisms, respectively. FEBS J. 2008 275 8 1889 1899 10.1111/j.1742‑4658.2008.06349.x 18341588
    [Google Scholar]
  58. Kamath A. Mehal W. Jain D. Colchicine-associated ring mitosis in liver biopsy and their clinical implications. J. Clin. Gastroenterol. 2008 42 9 1060 1062 10.1097/MCG.0b013e31803815b4 18391833
    [Google Scholar]
  59. Kyriakis J.M. Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: A 10-year update. Physiol. Rev. 2012 92 2 689 737 10.1152/physrev.00028.2011 22535895
    [Google Scholar]
  60. Kyriakis J.M. Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001 92 2 689 737 10.1152/physrev.2001.81.2.807
    [Google Scholar]
  61. Kyriakis J.M. Avruch J. Protein kinase cascades activated by stress and inflammatory cytokines. BioEssays 1996 18 7 567 577 10.1002/bies.950180708 8757935
    [Google Scholar]
  62. Xia Z Dickens M Raingeaud J Davis RJ Greenberg ME Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science (1979). 1995 270 5240 1326 1331 10.1126/science.270.5240.1326
    [Google Scholar]
  63. Sugiura R. Satoh R. Takasaki T. ERK: A double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells 2021 10 10 2509 10.3390/cells10102509 34685488
    [Google Scholar]
  64. Lim W. Jeong M. Bazer F.W. Song G. Coumestrol inhibits proliferation and migration of prostate cancer cells by regulating AKT, ERK1/2, and JNK MAPK cell signaling cascades. J. Cell. Physiol. 2017 232 4 862 871 10.1002/jcp.25494 27431052
    [Google Scholar]
  65. Alliana S.A. Menou L. Manié S. Antomarchi S.H. Millet M.A. Giuriato S. Ferrua B. Rossi B. Microtubule integrity regulates src-like and extracellular signal-regulated kinase activities in human pro-monocytic cells. Importance for interleukin-1 production. J. Biol. Chem. 1998 273 6 3394 3400 10.1074/jbc.273.6.3394 9452460
    [Google Scholar]
  66. Nair R.R. Schwarz LA. Microtubule-disrupting agents increase transgene expression in A549 cells through the activation of the Src and ERK kinase pathway. Mol. Ther. 2003 7 5
    [Google Scholar]
  67. Samarakoon R. Higgins P.J. MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. J. Cell Sci. 2002 115 15 3093 3103 10.1242/jcs.115.15.3093 12118065
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206352302241227031015
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Anticancer Properties of Phenylboronic Acid in Androgen-Dependent (LNCaP) and Androgen-Independent (PC3) Prostate Cancer Cells via MAP Kinases by 2D and 3D Culture Methods
Bentham Science Publishers ; https://doi.org/10.2174/0118715206352302241227031015
/content/journals/acamc/10.2174/0118715206352302241227031015
/content/journals/acamc/10.2174/0118715206352302241227031015
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  • Article Type:     Research Article
Keywords: electron microscopy ; ERK ; Prostate cancer ; LNCaP ; PC3 ; Phenylboronic acid ; p38 ; JNK

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