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Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress

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Abstract

Tubulin and deoxyribonucleic acid (DNA) are two potential targets for the development of cancer chemotherapeutic agents. Mana-Hox is a synthetic derivative of β-carboline, a structure relevant to marine sponge component, manzamine. In this study, Mana-Hox induced an inhibition of cell proliferation in several types of human cancer cell lines, including androgen-independent prostate cancer PC-3 and DU-145, hepatocellular carcinoma Hep3B and HepG2, and colorectal cancer HT-29 cells. The p53-null PC-3 cells were used for to anticancer mechanisms. Mana-Hox stimulated an increase of ataxia telangiectasia mutated (ATM) phosphorylation on Ser-1981, indicating the induction of DNA double-strand breaks. It also displayed an inhibitory effect on tubulin polymerization using tubulin turbidity assay and immunofluorescence identification. However, it only showed a minor inhibition on the activity of Aurora kinase and histone deacetylase. Mana-Hox induced mitotic arrest of the cell cycle identified by downregulation of cyclin E, cyclin A, and cyclin-dependent kinase 2 (Cdk2) and an increase of MPM-2 expression. Next, it caused Bcl-2 phosphorylation on Ser-70, downregulation of Mcl-1 expression, and activation of caspase-3, leading to apoptotic cell death. Notably, Mana-Hox was not a P-glycoprotein (P-gp) substrate and showed equipotent activity against P-gp-rich cancer cells. We conclude that Mana-Hox induces dual effects on DNA damage and tubulin depolymerization, leading to mitotic arrest and activation of mitochondria-mediated apoptotic pathways. Data provide evidence that the anticancer strategy of dual-action targets could be a potential anticancer approach.

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References

  • Adachi S, Obaya AJ, Han Z, Ramos-Desimone N, Wyche JH, Sedivy JM (2001) c-Myc is necessary for DNA damage-induced apoptosis in the G(2) phase of the cell cycle. Mol Cell Biol 21:4929–4937

    Article  PubMed  CAS  Google Scholar 

  • Andersen SS (2000) Spindle assembly and the art of regulating microtubule dynamics by MAPs and Stathmin/Op18. Trends Cell Biol 10:261–267

    Article  PubMed  CAS  Google Scholar 

  • Brozovic A, Osmak M (2007) Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett 251:1–16

    Article  PubMed  CAS  Google Scholar 

  • Drewes G, Ebneth A, Preuss U, Mandelkow E-M, Mandlekow E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89:297–308

    Article  PubMed  CAS  Google Scholar 

  • Dustin P (1980) Microtubules. Sci Am 243:66–76

    Article  PubMed  CAS  Google Scholar 

  • Ehrlichova M, Vaclavikova R, Ojima I, Pepe A, Kuznetsova LV, Chen J, Truksa J, Kovar J, Gut I (2005) Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 372:95–105

    Article  PubMed  CAS  Google Scholar 

  • Estevez LG, Gradishar WJ (2004) Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer. Clin Cancer Res 10:3249–3261

    Article  PubMed  CAS  Google Scholar 

  • Fumoleau P, Coudert B, Isambert N, Ferrant E (2007) Novel tubulin-targeting agents: anticancer activity and pharmacologic profile of epothilones and related analogues. Ann Oncol (Suppl 5):v9–v15

    Article  Google Scholar 

  • Gaiddon C, Jeannequin P, Bischoff P, Pfeffer M, Sirlin C, Loeffler JP (2005) Ruthenium (II)-derived organometallic compounds induce cytostatic and cytotoxic effects on mammalian cancer cell lines through p53-dependent and p53-independent mechanisms. J Pharmacol Exp Ther 315:1403–1411

    Article  PubMed  CAS  Google Scholar 

  • Graves PR, Lovly CM, Uy GL, Piwnica-Worms H (2001) Localization of human Cdc25C is regulated both by nuclear export and 14–3–3 protein binding. Oncogene 20:1839–1851

    Article  PubMed  CAS  Google Scholar 

  • Haldar S, Jena N, Croce CM (1995) Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci USA 92:4507–4511

    Article  PubMed  CAS  Google Scholar 

  • Hall D, Minton AP (2005) Turbidity as a probe of tubulin polymerization kinetics: a theoretical and experimental re-examination. Anal Biochem 345:198–213

    Article  PubMed  CAS  Google Scholar 

  • Hendrikse NH (2000) Monitoring interactions at ATP-dependent drug efflux pumps. Curr Pharm Des 6:1653–1668

    Article  PubMed  CAS  Google Scholar 

  • Ismail IH, Nyström S, Nygren J, Hammarsten O (2005) Activation of ataxia telangiectasia mutated by DNA strand break-inducing agents correlates closely with the number of DNA double strand breaks. J Biol Chem 280:4649–4655

    Article  PubMed  CAS  Google Scholar 

  • Jackson SJ, Singletary KW (2004) Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization. Carcinogenesis 25:219–227

    Article  PubMed  CAS  Google Scholar 

  • Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev 99:2467–2498

    Article  PubMed  CAS  Google Scholar 

  • Kim BJ, Ryu SW, Song BJ (2006) JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281:21256–21265

    Article  PubMed  CAS  Google Scholar 

  • Kremer CL, Schmelz M, Cress AE (2006) Integrin-dependent amplification of the G2 arrest induced by ionizing radiation. Prostate 66:88–96

    Article  PubMed  CAS  Google Scholar 

  • Ling YH, Tornos C, Perez-Soler R (1998) Phosphorylation of Bcl-2 is a marker of M phase events and not a determinant of apoptosis. J Biol Chem 273:18984–18991

    Article  PubMed  CAS  Google Scholar 

  • Lu PH, Kung FL, Kuo SC, Chueh SC, Guh JH (2006) Investigation of anti-tumor mechanisms of K2154: characterization of tubulin isotypes, mitotic arrest and apoptotic machinery. Naunyn Schmiedebergs Arch Pharmacol 374:223–233

    Article  PubMed  CAS  Google Scholar 

  • Maity A, McKenna WG, Muschel RJ (1994) The molecular basis for cell cycle delays following ionizing radiation: a review. Radiother Oncol 31:1–13

    Article  PubMed  CAS  Google Scholar 

  • Marinho J, Pedro M, Pinto DC, Silva AM, Cavaleiro JA, Sunkel CE, Nascimento MS (2008) 4′-Methoxy-2-styrylchromone a novel microtubule-stabilizing antimitotic agent. Biochem Pharmacol 75:826–835

    Article  PubMed  CAS  Google Scholar 

  • McGrath JL (2005) Dynein motility: four heads are better than two. Curr Biol 15:R970–R972

    Article  PubMed  CAS  Google Scholar 

  • Moinet-Hedin V, Tabka T, Poulain L, Godard T, Lechevrel M, Saturnino C, Lancelot JC, Le Talaer JY, Gauduchon P (2000) Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs. Anticancer Drug Des 15:109–118

    PubMed  CAS  Google Scholar 

  • Montecucco A, Biamonti G (2007) Cellular response to etoposide treatment. Cancer Lett 252:9–18

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Uenaka T, Nagasu T, Sugumi H, Yamaguchi A, Kotake Y, Okada T, Kamata J, Niijima J, Taniguchi T, Koyanagi N, Yoshino H, Kitoh K, Yoshimatsu K (2003) A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo. Cancer Sci 94:119–124

    Article  PubMed  CAS  Google Scholar 

  • Nguyen H-L, Gruber D, McGraw T, Sheetz MP, Bulinski JC (1998) Stabilization and functional modulation of microtubules by microtubule-associated protein 4. Biol Bull 194:354–357

    Article  PubMed  CAS  Google Scholar 

  • Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22:7280–7295

    Article  PubMed  CAS  Google Scholar 

  • Pellegrini F, Budman DR (2005) Review: tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest 23:264–273

    Article  PubMed  CAS  Google Scholar 

  • Perez-Stable C (2006) 2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells. Cancer Lett 231:49–64

    Article  PubMed  CAS  Google Scholar 

  • Pu YS, Hsieh MW, Wang CW, Liu GY, Huang CY, Lin CC, Guan JY, Lin SR, Hour TC (2006) Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells. Biochem Pharmacol 71:751–760

    Article  PubMed  CAS  Google Scholar 

  • Ramnath N, Khushalani N, Toth K, Litwin AM, Intengan ME, Slocum HK, Pendyala L, Smith PF, Stewart CC, Hoffman JL, Javle MM, Berdzik J, Creaven PJ, Rustum YM (2005) S-phase modulation by irinotecan: pilot studies in advanced solid tumors. Cancer Chemother Pharmacol 56:447–454

    Article  PubMed  CAS  Google Scholar 

  • Ray S, Shyam S, Fraizer GC, Almasan A (2007) S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells. Mol Cancer Ther 6:1368–1378

    Article  PubMed  CAS  Google Scholar 

  • Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12:440–450

    Article  PubMed  CAS  Google Scholar 

  • Sedletska Y, Giraud-Panis MJ, Malinge JM (2005) Cisplatin is a DNA-damaging antitumour compound triggering multifactorial biochemical responses in cancer cells: importance of apoptotic pathways. Curr Med Chem Anticancer Agents 5:251–265

    Article  PubMed  CAS  Google Scholar 

  • Shiah HS, Lee WS, Juang SH, Hong PC, Lung CC, Chang CJ, Chou KM, Chang JY (2007) Mitochondria-mediated and p53-associated apoptosis induced in human cancer cells by a novel selenophene derivative, D-501036. Biochem Pharmacol 73:610–619

    Article  PubMed  CAS  Google Scholar 

  • Silverman JA (1999) Multidrug-resistance transporters. Pharm Biotechnol 12:353–386

    Article  PubMed  CAS  Google Scholar 

  • Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112

    Article  PubMed  CAS  Google Scholar 

  • Tanaka T, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z (2006) Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. Cell Cycle 5:1940–1945

    PubMed  CAS  Google Scholar 

  • Tanaka T, Huang X, Halicka HD, Zhao H, Traganos F, Albino AP, Dai W, Darzynkiewicz Z (2007) Cytometry of ATM activation and histone H2AX phosphorylation to estimate extent of DNA damage induced by exogenous agents. Cytometry A 71:648–661

    PubMed  Google Scholar 

  • Tu LC, Chou CK, Chen CY, Chang YT, Shen YC, Yeh SF (2004) Characterization of the cytotoxic mechanism of Mana-Hox, an analog of manzamine alkaloids. Biochim Biophys Acta 1672:148–156

    PubMed  CAS  Google Scholar 

  • Tu LC, Chen CS, Hsiao IC, Chern JW, Lin CH, Shen YC, Yeh SF (2005) The beta-carboline analog Mana-Hox causes mitotic aberration by interacting with DNA. Chem Biol 12:1317–1324

    Article  PubMed  CAS  Google Scholar 

  • Uhm JE, Lim HY, Kim WS, Choi HY, Lee HM, Park BB, Park K, Kang WK (2007) Paclitaxel with cisplatin as salvage treatment for patients with previously treated advanced transitional cell carcinoma of the urothelial tract. Neoplasia 9:18–22

    Article  PubMed  CAS  Google Scholar 

  • Urist M, Tanaka T, Poyurovsky MV, Prives C (2004) p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev 18:3041–3054

    Article  PubMed  CAS  Google Scholar 

  • Wang LG, Liu XM, Kreis W, Budman DR (1999) The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44:355–361

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Wiltshire T, Senft J, Reed E, Wang W (2007) Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol 73:469–480

    Article  PubMed  CAS  Google Scholar 

  • Warner SL, Munoz RM, Stafford P, Koller E, Hurley LH, Von Hoff DD, Han H (2006) Comparing Aurora A and Aurora B as molecular targets for growth inhibition of pancreatic cancer cells. Mol Cancer Ther 5:2450–2458

    Article  PubMed  CAS  Google Scholar 

  • Wetzel M, Premkumar DR, Arnold B, Pollack IF (2005) Effect of trichostatin A, a histone deacetylase inhibitor, on glioma proliferation in vitro by inducing cell cycle arrest and apoptosis. J Neurosurg 103(6 Suppl):549–556

    PubMed  Google Scholar 

  • Yazlovitskaya EM, Persons DL (2003) Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin. Anticancer Res 23:2275–2279

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by a research grant of the National Science Council of the Republic of China (NSC 95–2323-B-002–006 and NSC 96–2323-B-002–004).

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Authors and Affiliations

  1. School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan

    Che-Jen Hsiao, Yunn-Fang Ho, Wei-Ling Chang, Yi-Cheng Chen, Ya-Ching Shen & Jih-Hwa Guh

  2. Department of Life Sciences and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan

    Che-Jen Hsiao & Ping-Chiang Lyu

  3. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan

    John T.-A. Hsu

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  1. Che-Jen Hsiao
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Correspondence to Jih-Hwa Guh.

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Hsiao, CJ., Ho, YF., Hsu, J.TA. et al. Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress. Naunyn-Schmied Arch Pharmacol 378, 599–608 (2008). https://doi.org/10.1007/s00210-008-0330-7

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